Methods and compositions for treating metabolic syndrome

ABSTRACT

Provided are methods, compositions, systems, and kits for treating metabolic syndrome or a disorder associated with metabolic syndrome, e.g., obesity, dyslipidemia, and/or a diabetic condition, comprising administering systemically to a subject one or more compounds of the Formula (I) and/or (II): 
                         
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof, wherein  , L, R 1 , R 2 , Z, X, A and B are defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of and claims priority under35 U.S.C. § 120 to U.S. patent application Ser. No. 14/509,680, filedOct. 8, 2014, now U.S. Pat. No. 9,504,695, which is a continuation ofand claims priority under 35 U.S.C. § 120 to U.S. patent applicationSer. No. 13/980,179, filed Sep. 19, 2013, now U.S. Pat. No. 9,089,579,which is a national stage filing under 35 U.S.C. § 371 of internationalPCT application, PCT/US2012/021692, filed Jan. 18, 2012, which claimspriority under 35 U.S.C. § 119(e) to U.S. Provisional Patent ApplicationSer. No. 61/434,337, filed Jan. 19, 2011, each of which is incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to methods and compositions for treatingand/or preventing metabolic syndrome or a disorder associated withmetabolic syndrome, e.g., obesity, dyslipidemia, and/or a diabeticcondition, in the body of a subject. More specifically, obesity,dyslipidemia, and/or a diabetic condition may be treated and/orprevented by administering to a subject a therapeutically effectiveamount of one or more compounds described herein.

BACKGROUND OF THE INVENTION

Metabolic syndrome, also known as metabolic syndrome X, cardiometabolicsyndrome, syndrome X, and insulin resistance syndrome, is a cluster ofmedical disorders that, when occurring together, increase the risk ofdiabetes and cardiovascular disease. See, e.g., Alberti et al.Circulation 2009; 120:1640-1645. Metabolic syndrome affects 35-40% ofAmerican adults, and prevalence increases with age. Principal disordersassociated with or used in the diagnosis of metabolic syndrome include,but are not limited to, obesity, dyslipidemia, and diabetic conditions,and conditions associated with these disorders, such as elevated glucoselevels and hypertension.

Obesity is a risk factor for a wide array of diseases, for example, type2 diabetes, hypertension, hyperlipidemia, coronary artery disease,stroke, breast and colon cancer, sleep apnea, gall bladder disease,gastroesophogeal reflux disease, fatty liver disease, gout, andthromboembolism. Blood pressure, blood sugar, serum cholesterol, andserum uric acid are usually higher in obese people than in those ofnormal weight. Despite increased awareness of these health risks, theprevalence of obesity has risen steadily for decades in manyindustrialized nations. As a result, there has been considerableinterest in ways to reduce obesity.

The excess body fat of obese subjects is typically deposited in adiposetissue. This tissue and its principal cell type, the adipocyte, havebeen implicated in a wide array of diseases, for example, metabolicsyndrome, type 2 diabetes, atherosclerosis, fatty liver, hepaticfibrosis, breast cancer, inflammation, depression, and dementia. Thecausative role of adipose tissue in these diseases appears to involvemediators such as adiponectin, resistin, tumor necrosis factor alpha(TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), fibrinogen,plasminogen activator inhibitor-1 (PAI-1), and/or C-terminal bindingprotein (CtBP). As a result, the adipocyte per se, rather than being amere storehouse for calories, plays a pathogenic role in many diseasesand represents a target for therapeutic intervention.

A number of medical conditions are considered to be causes of obesity orlocal excesses of body fat. Examples include drug-induced obesity,hypothyroidism, pseudohypoparathyroidism, hypothalamic obesity,polycystic ovarian disease, depression, binge eating, Prader-Willisyndrome, Bardet-Biedl syndrome, Cohen syndrome, Down syndrome, Turnersyndrome, growth hormone deficiency, growth hormone resistance, leptindeficiency or resistance, HIV lipodystrophy, and Cushing syndrome andpseudo-Cushing syndrome (i.e., characteristic syndrome of excess bodyfat and other findings due to excessive endogenous or exogenouscorticosteroid levels). Some of these conditions, for example, Cushingsyndrome, pseudo-Cushing syndrome, and HIV-related lipodystrophy, areassociated with other features of metabolic syndrome, such as insulinresistance and dyslipidemia.

Medications known to cause obesity or local excess of body fat includecortisol and analogs, other corticosteroids, megace, sulfonylureas,antiretrovirals, tricyclic antidepressants, monoamine oxidaseinhibitors, selective serotonin reuptake inhibitors, oralcontraceptives, insulin, risperidone, clozapine, and thiazolidinediones.Some of these medications, for example, corticosteroids andantiretrovirals, are associated with other features of metabolicsyndrome, such as insulin resistance and dyslipidemia.

Changes in hormonal status, including physiologic changes such aspregnancy or menopause, may result in obesity in a subject. Smokingcessation commonly leads to weight gain and obesity. Trauma may favorthe accumulation of excess body fat by virtue of immobility or disuse ofan extremity. Similar problems may affect an immobile subject, such asan astronaut or bedridden subject who is immobilized for an extendedperiod of time. Some tumors, for example, lipomas, are characterized bycollections of fat cells that may be amenable to methods to reduce bodyfat. Even in the absence of underlying pathology, a subject may havecosmetic concerns about body fat. These can usually be attributed toconstitutional or hereditary factors, developmental history, age,gender, diet, alcohol use, or other aspects of lifestyle.

A number of methods have been developed to reduce obesity. It is helpfulto classify these methods as extractive, metabolic, or adipolytic.Extractive methods, such as lipoplasty (e.g., liposuction) or localexcision, are methods whereby fat is physically removed from areas ofinterest. Such methods do not appear to correct other features ofmetabolic syndrome. They are costly and may involve scars, postsurgicaldeformity or regression, discomfort, infection, and other adversereactions.

In contrast to extractive methods, metabolic methods, which includemedications, nutritional supplements, devices, bariatric surgery, andexercise or other body treatment, seek to modify the subject'smetabolism (e.g., whether caloric intake, expenditure, or both) suchthat there is a net loss of fat in the subject. A disadvantage ispotential concomitant loss of water, carbohydrates, protein, vitamins,minerals, and other nutrients. Furthermore, traditional diet medicationsmay have undesired side effects, for example, palpitations, tremor,insomnia, and/or irritability in a subject who uses stimulants asappetite suppressants. Drawbacks of surgery are mentioned above. Despitesalubrious value, the traditional metabolic methods of diet and exerciseare not practical for everybody.

Adipolytic methods aim to cause breakdown of adipocytes and/or theirlipid contents. For example, fat deposits can be reduced by exposure tocold temperature or to deoxycholate, a solubilizer which lyses cellmembranes and results in local necrosis. Drawbacks of these methods caninclude poor discrimination between adipose and other nearby tissues,barriers to delivery that require hypodermic needles or specialequipment, and adverse effects such as necrosis, inflammation, and pain.

Fat circulates in the blood in various lipid and lipoprotein forms.Common measures of lipid concentration in the blood include serumtriglycerides, serum total cholesterol, serum low density lipoprotein(LDL), and serum high density lipoprotein (HDL). These lipidconcentrations are heavily influenced by diet and metabolism.

Dyslipidemia is an abnormality in one or more lipid or lipoproteinlevels in the blood. Dyslipidemia comprises one or more of: elevatedserum triglycerides, elevated total cholesterol, elevated low densitylipoprotein (LDL), reduced high density lipoprotein (HDL), and/orabnormal distribution of serum lipoproteins as measured, for example, bynuclear magnetic resonance spectroscopy.

Elevations of some lipid concentrations, e.g. triglycerides and/or LDL,are risk factors for diseases such as atherosclerosis, coronary heartdisease, stroke, neurovascular disease, peripheral vascular disease, anddiabetes. Conversely, abnormally low levels of HDL are associated withcardiovascular disease. Numerous medications have been developed totreat dyslipidemia, e.g., by reducing lipid and/or lipoproteinconcentrations. Of these, the “statins” or HMG CoA reductase inhibitors,which decrease LDL levels, are well known examples. For many patients,however, the currently available therapies are insufficient orunsuitable, for example, due to side effects such as myopathy.

Diabetic conditions include diabetes mellitus and pre-diabetes. Diabetesmellitus, which comprises type 1 diabetes and type 2 diabetes, is acondition characterized by hyperglycemia resulting from the body'sinability to use blood glucose for energy. Pre-diabetes is a conditionwherein blood glucose levels are higher than normal but not high enoughfor a diagnosis of diabetes; people with pre-diabetes are at increasedrisk for developing type 2 diabetes. A common feature of type 2 diabetesand pre-diabetes, insulin resistance, is a physiological conditionwherein insulin becomes less effective at lowering blood sugar levels,resulting in elevated blood sugar levels. Impaired glucose tolerance isa condition wherein glucose intake (for example, orally orintravenously) results in abnormally elevated blood sugar levels.Glucose tolerance can be measured, for example, by systematic challengewith an oral glucose load (oral glucose tolerance test). “Diabeticcomplications” include chronic and acute complications of diabetes.Chronic complications include atherosclerosis, stroke, myocardialischemia, nephropathy, peripheral neuropathy, retinopathy, infection,foot ulcers, and death. Acute complications include metabolic acidosis,nonketotic hypersosmolar state, volume depletion, coma, and death.

Local reduction of adipose tissue does not treat dyslipidemia ordiabetes. The peer-reviewed literature has even expressed concern thatlysis of adipocytes could dump lipids into the bloodstream and therebyincrease serum lipid concentrations. See, e.g., Klein et al, Lasers SurgMed 2009; 41:785-790. In one clinical trial, local reduction of flankfat by cryolipolysis did not cause any change in serum triglycerides,total cholesterol, LDL, or HDL See, e.g., Klein et al, Lasers Surg Med2009; 41:785-790. Likewise, local reduction of hip fat by laserlipolysis caused no change in these parameters. See, e.g., Mordon et al,J Cosmet Laser Ther 2009; 11:74-74. Furthermore, surgical removal ofsubcutaneous fat in hamsters actually increased serum triglyceridelevels and insulin resistance due to compensatory deposition ofintraabdominal fat. See, e.g., Weber et al, Am J Physiol Regul IntegrComp Physiol 2000; 279:R936-943. Even large-volume lipectomy, which isdistinct from local fat reduction, does not consistently elicit areduction in serum lipids or serum glucose. In one report, 9 of 10patients who underwent large-volume lipectomy showed reduced serum totalcholesterol, but no reduction in triglycerides, or in the HDL:LDL ratio.See, e.g., Baxter, Aesthet Surg J 1997; 17:213-215. Surgical lipectomyin Zucker rats showed mean reductions in serum triglycerides and totalcholesterol, but no reductions in serum glucose. See, e.g., Liszka etal, Plast Reconstr Surg 1998; 102:1122-1127.

Even systemic medical therapy for weight loss does not necessarily leadto absolute benefits in serum lipids or glucose. A landmark randomizedcontrolled trial studied the effects of two years of systemic Orlistattherapy in obese adults. See Davidson et al, JAMA 1999; 281:235-243.After two years, subjects randomized to Orlistat 120 mg three timesdaily lost 8.8% of baseline body weight, compared to 5.8% in the placebogroup (p<0.001). However, this weight loss was not accompanied by anyabsolute improvement in serum lipids or serum glucose.

Therefore, there is a need for new approaches including new methods andcompositions for treating and/or preventing metabolic syndrome andassociated conditions, for example, treating or preventing obesity,dyslipidemia, and/or diabetic conditions, in a subject in need thereof.These approaches may include reducing fat and/or adipocytes in thesubject and optionally also reducing levels of undesired serum lipidsand/or serum glucose in the bloodstream.

SUMMARY OF THE INVENTION

The present invention arises in part from a new finding that systemicadministration of certain F-series prostaglandins to obese,dyslipidemic, and/or diabetic subjects has a beneficial effect on thesubjects. The effects observed in subjects systemically treated withsuch prostaglandins include reduced obesity, reduced weight gain, reduceserum triglycerides, reduced serum LDL, increased serum HDL, reducedserum glucose, and/or improved glucose tolerance.

The present invention also arises from the observation that systemicadministration of certain F-series prostaglandin compounds to obesesubjects reduces weight of the subject and/or reduces weight gain inthose subjects.

The present invention also arises from the identification of certainparticularly useful species from among the genus of F-seriesprostaglandins for the purposes of the invention.

U.S. Pat. No. 7,666,912, contemplates non-systemic topical,subcutaneous, intramuscular, and intralesional administration of certainprostaglandins, e.g., bimatoprost, latanoprost, and tavoprost, wouldlocally reduce fat in a subject at the site of administration. Forinstance, the Examples of U.S. Pat. No. 7,666,912 contemplatesnon-systemic transdermal application of bimatoprost at concentrations of0.003%, 0.03%, or 0.3%, would locally reduce fat in a subject at thesite of administration. The inventor has now discovered that while 0.3%topical bimatoprost locally reduces subcutaneous fat in a subject, theisopropyl ester and free acid of bimatoprost are significantly moreeffective in reducing subcutaneous fat. The inventor has furtherdiscovered that transdermal administration of bimatoprost at 0.3% has noeffect on systemic reduction of fat, while the corresponding free acidand isopropyl ester have dramatic systemic effects and systemic fatreduction. The inventor has further found that even higher doses, e.g.,0.7% dose of latanoprost, may be desirable in order to obtain systemiceffects transdermally. Furthermore, the inventor discovered that neithersubcutaneous nor intraaperitoneal administration of bimatoprost had anysignificant effect on fat reduction. The inventor contemplates that theobserved benefits of transdermal administration may be similarlyobserved if a time-release formulation, such as a controlled orsustained release, for oral or subcutaneous administration is delivered.Other routes of administration for various time-release formulations arecontemplated. These findings and observations, which are the basis forthe present invention, are indeed surprising and unexpected, especiallyconsidering U.S. Pat. No. 7,666,912 dissuades from systemicallyadministering such compounds.

In one aspect, the invention provides methods, compositions, kits, andsystems for treating or preventing metabolic syndrome in a subject inneed thereof, the method comprising administering systemically to thesubject one or more compounds of Formula (I) or (II), as described belowand herein, or a pharmaceutically acceptable salt, hydrate, solvate,stereoisomer, polymorph, tautomer, isotopically enriched derivative, orprodrug thereof.

In certain embodiments, the compound for use in the present invention isof Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof;wherein:

each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration;

A is optionally substituted C₁₋₁₀alkylene, optionally substitutedC₂₋₁₀alkenylene, or optionally substituted C₂₋₁₀ alkynylene, wherein thealkylene, alkenylene, or alkynylene group is optionally interrupted byone or more —O— or —S— groups;

B is hydrogen, optionally substituted C₃₋₇carbocyclyl, optionallysubstituted 3-8-membered-heterocyclyl, optionally substituted5-14-membered-heteroaryl, optionally substituted C₆₋₁₀aryl, optionallysubstituted C₁₋₃₀alkyl, optionally substituted C₂₋₃₀alkenyl, oroptionally substituted C₂₋₃₀alkynyl;

X is —OR₄, —SR₄, or —N(R₄)₂, wherein each instance of R₄ isindependently hydrogen, optionally substituted C₁₋₃₀alkyl, optionallysubstituted C₂₋₃₀alkenyl, optionally substituted C₂₋₃₀alkynyl, —C(═O)R₅,or —C(═O)OR₅, wherein R₅ is optionally substituted C₁₋₃₀alkyl,optionally substituted C₂₋₃₀alkenyl, or optionally substitutedC₂₋₃₀alkynyl, or two R₄ groups are joined to form an optionallysubstituted 3-8-membered-heterocyclyl or optionally substituted5-14-membered-heteroaryl ring;

Z is ═O, ═S, or ═NR_(Z), wherein R_(Z) is selected from hydrogen, anamino protecting group, —OH, substituted hydroxyl, optionallysubstituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇carbocyclyl,optionally substituted 3-8-membered-heterocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl, or Zrepresents two hydrogen atoms; and

one of R₁ and R₂ is ═O, —OH, or a —O(CO)R₆ group and the other one is—OH or —O(CO)R₆, or R₁ is ═O and R₂ is H, wherein R₆ is a an optionallysubstituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl, optionallysubstituted C₂₋₂₀ alkynyl, or —(CH₂)_(m)R₇ wherein m is 0 or an integerof between 1-10, inclusive, and R₇ is optionally substitutedC₃₋₇carbocyclyl, optionally substituted 3-8-membered-heterocyclyl,optionally substituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl.

Exemplary compounds of Formula (I) include, but are not limited to:

also referred to herein as CAY10509;

also referred to herein as CAY10509 free acid;

also referred to herein as 17-phenyl trinor prostaglandin F2α ethylamide, or bimatoprost;

also referred to herein as 17-phenyl trinor prostaglandin F2α isopropylester, or bimatoprost isopropyl ester;

also referred to herein as 17-phenyl trinor prostaglandin F2α, orbimatoprost free acid;

also referred to herein as fluprostenol isopropyl ester, or travoprost;

also referred to herein as travoprost free acid;

also referred to herein as 17-phenyl-13,14-dihydro trinor prostaglandinF2α isopropyl ester, or latanoprost;

also referred to herein as latanoprost free acid;

also referred to herein as tafluprost;

also referred to herein as tafluprost free acid;

also referred to as AL-16082;or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof.

In certain embodiments, the compound for use in the present invention isof Formula (II):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof;wherein:

L is a group of the formula

wherein

represents a single bond or a double bond, which can be in the cis ortrans configuration;

A is optionally substituted C₁₋₁₀alkylene, optionally substitutedC₂₋₁₀alkenylene, or optionally substituted C₂₋₁₀ alkynylene, wherein thealkylene, alkenylene, or alkynylene group is optionally interrupted byone or more —O— or —S— groups;

B is hydrogen, optionally substituted C₃₋₇carbocyclyl, optionallysubstituted 3-8-membered-heterocyclyl, optionally substituted5-14-membered-heteroaryl, optionally substituted C₆₋₁₀aryl, optionallysubstituted C₁₋₃₀alkyl, optionally substituted C₂₋₃₀alkenyl, oroptionally substituted C₂₋₃₀alkynyl;

X is —OR₄, —SR₄, or —N(R₄)₂, wherein each instance of R₄ isindependently hydrogen, optionally substituted C₁₋₃₀alkyl, optionallysubstituted C₂₋₃₀alkenyl, optionally substituted C₂₋₃₀alkynyl, —C(═O)R₅,or —C(═O)OR₅, wherein R₅ is optionally substituted C₁₋₃₀alkyl,optionally substituted C₂₋₃₀alkenyl, or optionally substitutedC₂₋₃₀alkynyl, or two R₄ groups are joined to form an optionallysubstituted 3-8-membered-heterocyclyl or optionally substituted5-14-membered-heteroaryl ring;

Z is ═O, ═S, or ═NR_(Z), wherein R_(Z) is selected from hydrogen, anamino protecting group, —OH, substituted hydroxyl, optionallysubstituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇carbocyclyl,optionally substituted 3-8-membered-heterocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl, or Zrepresents two hydrogen atoms; and

R₁ is ═O, —OH, or —O(CO)R₆, wherein R₆ is a an optionally substitutedC₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substitutedC₂₋₂₀ alkynyl, or —(CH₂)_(m)R₇ wherein m is 0 or an integer of between1-10, inclusive, and R₇ is optionally substituted C₃₋₇carbocyclyl,optionally substituted 3-8-membered-heterocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl.

Exemplary compounds of Formula (II) include, but are not limited to,

also referred to as AL-12182; and

also referred to as AL-12182 free acid;or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, Y, X, and n are as defined herein.

In certain embodiments, the compound of Formula (I) or (II) is a prodrugof any one of the compounds described herein. Exemplary prodrugs includeesters, amides, and/or thioamides of the parent free acid and acylgroups present on the pentacyclic hydroxyl groups.

Compounds described herein are members of a class that has beenpreviously described, for example, in U.S. Pat. Nos. 4,599,353,5,296,504, 5,422,368, 5,688,819, 6,232,344, 6,403,649, and 7,666,912,Selliah et al (Bioorg Med Chem Lett 2004; 14:4525-4528), and Feng et al(Bioorg Med Chem 2009; 17:576-584), each of which is incorporated hereinby reference. This class of compounds, which are analogs ofProstaglandin F2α, is known to reduce intraocular pressure in the eye.

In a second aspect, the invention provides methods, compositions, kits,and systems for treating or preventing a disorder associated with orused in the diagnosis of metabolic syndrome, such as obesity,dyslipidemia, and/or a diabetic condition, and/or a condition associatedwith these disorders, in a subject in need thereof, the methodcomprising administering to the subject one or more compounds of Formula(I) or (II), or a pharmaceutically acceptable salt, hydrate, solvate,stereoisomer, polymorph, tautomer, isotopically enriched derivative, orprodrug thereof.

In a third aspect, the invention provides a methods, compositions, kits,and systems for treating or preventing obesity in a subject, the methodincluding administering to a subject one or more compounds of Formula(I) or (II), or a pharmaceutically acceptable salt, hydrate, solvate,stereoisomer, polymorph, tautomer, isotopically enriched derivative, orprodrug thereof. In some embodiments, the subject has obesity but doesnot suffer from metabolic syndrome.

In certain embodiments, the method of treating obesity comprisesreducing adipocytes. In certain embodiments, the subject also suffersfrom or is likely to suffer from an adipocyte-related disease. Incertain embodiments, the adipocyte-related disease is selected from thegroup consisting of metabolic syndrome, excess body fat (e.g., beingoverweight, obesity), dyslipidemia, hypercholesterolemia,hypertriglyceridemia, diabetes (e.g., type 2 diabetes), atherosclerosis,vascular disease, coronary artery disease, stroke, cerebrovasculardisease, peripheral vascular disease, fatty liver disease, hepaticfibrosis, pancreatitis, cancer (e.g., breast cancer, uterine cancer,colon cancer, colorectal cancer, kidney cancer, esophageal cancer),inflammation or inflammatory disease, depression, and dementia. Incertain embodiments, the adipocyte-related disease is selected from thegroup consisting of metabolic syndrome, diabetes (e.g., type 2diabetes), liver disease, atherosclerosis, fatty liver disease, hepaticfibrosis, breast cancer, colon cancer, inflammation or inflammatorydisease, depression, and dementia.

In a fourth aspect, the invention provides methods, compositions, kits,and systems for treating or preventing dyslipidemia, comprisingadministering to a subject one or more compounds of Formula (I) or (II),or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof. In some embodiments, the subject has dyslipidemia but does notsuffer from metabolic syndrome.

In certain embodiments, treating dyslipidemia comprises one or more ofreducing serum triglycerides, reducing serum total cholesterol, reducingserum lipoprotein (e.g., low density lipoprotein (LDL), very low densitylipoprotein (VLDL)), and/or increasing serum high density lipoprotein(HDL). In certain embodiments, treating dyslipidemia comprises reducingthe concentration of lipid (e.g., triglycerides, cholesterol,lipoproteins, e.g., low density lipoprotein (LDL), and/or very lowdensity lipoprotein (VLDL)) in the blood of the subject. In certainembodiments, the subject suffers from or is likely to suffer from adisease, disorder, or condition associated with dyslipidemia. In certainembodiments, the subject suffers from or is likely to suffer from adisease, disorder, or condition selected from the group consisting ofdyslipidemia, hypercholesterolemia, hypertriglyceridemia, a heritabledisorder characterized at least in part by one or more abnormal serumlipid levels (e.g., familial hypercholesterolemia, familialhypertriglyceridemia), excess body fat (e.g., overweight, obesity),metabolic syndrome, vascular disease, atherosclerosis, coronary arterydisease, stroke, cerebrovascular disease, peripheral vascular disease,metabolic syndrome, diabetes (e.g., type 2 diabetes), fatty liverdisease, hepatic fibrosis, pancreatitis, cancer (e.g., breast cancer,uterine cancer, colon cancer, colorectal cancer, kidney cancer,esophageal cancer), inflammation or inflammatory disease, depression,and dementia.

In a fifth aspect, the invention provides methods, compositions, kits,and systems for treating and/or preventing a diabetic condition,comprising administering to a subject one or more compounds of Formula(I) or (II), or a pharmaceutically acceptable salt, hydrate, solvate,stereoisomer, polymorph, tautomer, isotopically enriched derivative, orprodrug thereof. In some embodiments, the subject has a diabeticcondition but does not suffer from metabolic syndrome.

In certain embodiments, treating a diabetic condition comprises reducingserum glucose, reducing glycated hemoglobin levels, reducing seruminsulin, increasing insulin sensitivity, improving glucose tolerance(e.g., reducing the glucose levels measured during a glucose tolerancetest), reducing a subject's need for another medication (e.g., insulin)to maintain normal blood sugar levels, and/or treating or preventing adiabetic complication.

In certain embodiments, the diabetic subject being treated suffers fromor is likely to suffer from a disease, disorder or condition selectedfrom the group consisting of type 2 diabetes mellitus, type 1 diabetesmellitus, prediabetes, hyperglycemia, insulin resistance,hyperinsulinemia, diabetic nephropathy, diabetic retinopathy, diabeticneuropathy, atherosclerosis, coronary artery disease, stroke, myocardialischemia, myocardial infarction, diabetic myocardial small vesseldisease, diabetic gastroparesis, diabetic hearing loss, a diabetic skindisease, a diabetes-related infection, diabetic oral disease (e.g.,gingivitis), diabetic acidosis (e.g., diabetic ketoacidosis), nonketotichyperosmolar state, and diabetic foot ulcer.

For any of the inventive methods or compositions, in certainembodiments, the route of administering is selected from the groupconsisting of topical (e.g., transdermal), enteral (e.g., oral), andparenteral (e.g., subcutaneous) administration. In certain embodiments,the route of administration is transdermal. In certain embodiments, thecompound is administered in a lipophilic excipient. The foregoingaspects and embodiments of the invention may be more fully understood byreference to the following Definitions, Figures, Detailed Description,Examples, and the Claims.

DEFINITIONS

Chemical definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Certain compounds as described herein can comprise one or moreasymmetric centers, and thus can exist in various isomeric forms, e.g.,enantiomers and/or diastereomers. The compounds provided herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer. Incertain embodiments, the compounds as described herein are enantiopurecompounds. In certain other embodiments, mixtures of stereoisomers areprovided.

Furthermore, certain compounds, as described herein may have one or moredouble bonds that can exist as either the cis or trans, or the E or Zisomer, unless otherwise indicated. The invention additionallyencompasses the compounds as individual isomers substantially free ofother isomers, and alternatively, as mixtures of various isomers, e.g.,racemic mixtures of E/Z isomers or mixtures enriched in one E/Z isomer.

The terms “enantiomerically enriched,” “enantiomerically pure” and“non-racemic,” as used interchangeably herein, refer to compositions inwhich the percent by weight of one enantiomer is greater than the amountof that one enantiomer in a control mixture of the racemic composition(e.g., greater than 1:1 by weight). For example, an enantiomericallyenriched preparation of the (S)-enantiomer, means a preparation of thecompound having greater than 50% by weight of the (S)-enantiomerrelative to the (R)-enantiomer, more preferably at least 75% by weight,and even more preferably at least 80% by weight. In some embodiments,the enrichment can be much greater than 80% by weight, providing a“substantially enantiomerically enriched,” “substantiallyenantiomerically pure” or a “substantially non-racemic” preparation,which refers to preparations of compositions which have at least 85% byweight of one enantiomer relative to other enantiomer, more preferablyat least 90% by weight, and even more preferably at least 95% by weight.In preferred embodiments, the enantiomerically enriched composition hasa higher potency with respect to therapeutic utility per unit mass thandoes the racemic mixture of that composition. Enantiomers can beisolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred enantiomerscan be prepared by asymmetric syntheses. See, for example, Jacques, etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); andWilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein, alone or as part of another group, “alkyl” refers to aradical of a straight-chain or branched saturated hydrocarbon grouphaving from 1 to 30 carbon atoms (“C₁₋₃₀ alkyl”). In some embodiments,an alkyl group has 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). In someembodiments, an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀ alkyl”). Insome embodiments, an alkyl group has 1 to 6 carbon atoms (“C₁₋₆ alkyl”).In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C₁₋₅alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms(“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbonatoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1 to 2carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl group has 1carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groups includemethyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄),tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Unless otherwise specified, eachinstance of an alkyl group is independently unsubstituted(“unsubstituted alkyl”) or substituted (“substituted alkyl”) aresubstituted with one or more substituents. In certain embodiments, thealkyl group is an unsubstituted C₁₋₆ alkyl (e.g., —CH₃). In certainembodiments, the alkyl group is a substituted C₁₋₆ alkyl.

As used herein “perhaloalkyl” or “halosubstituted alkyl” as definedherein refers to an alkyl group having from 1 to 10 carbon atoms whereinall of the hydrogen atoms are each independently replaced halogen, e.g.,selected from fluoro, bromo, chloro or iodo (“C₁₋₁₀ perhaloalkyl”). Insome embodiments, the alkyl moiety has 1 to 6 carbon atoms (“C₁₋₆perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 5 carbonatoms (“C₁₋₅ perhaloalkyl 1”). In some embodiments, the alkyl moiety has1 to 4 carbon atoms (“C₁₋₄ perhaloalkyl”). In some embodiments, thealkyl moiety has 1 to 3 carbon atoms (“C₁₋₃ perhaloalkyl”). In someembodiments, the alkyl moiety has 1 to 2 carbon atoms (“C₁₋₂perhaloalkyl”). In some embodiments, all of the hydrogen atoms are eachreplaced with fluoro. In some embodiments, all of the hydrogen atoms areeach replaced with chloro. Examples of perhaloalkyl groups include —CF₃,—CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl and the like.

As used herein, “alkyloxy” refers to an alkyl group, as defined herein,substituted with an oxygen atom, wherein the point of attachment is theoxygen atom. In certain embodiments, the alkyl group has 1 to 6 carbonatoms (“C₁₋₆ alkyloxy”). In some embodiments, the alkyl group has 1 to 4carbon atoms (“C₁₋₄ alkyloxy”). Examples of C₁₋₄ alkyloxy groups includemethoxy (C₁), ethoxy (C₂), propoxy (C₃), isopropoxy (C₃), butoxy (C₄),tert-butoxy (C₅) and the like. Examples of C₁₋₆ alkyloxy groups includethe aforementioned C₁₋₄ alkyloxy groups as well as pentyloxy (C₅),isopentyloxy (C₅), neopentyloxy (C₅), hexyloxy (C₆) and the like. Unlessotherwise specified, each instance of the alkyl moiety of the alkyloxygroup is independently unsubstituted (“unsubstituted alkyloxy”) orsubstituted (“substituted alkyloxy”) with one or more substituents. Incertain embodiments, the alkyloxy group is an unsubstituted C₁₋₆alkyloxy. In certain embodiments, the alkyloxy group is a substitutedC₁₋₆ alkyloxy.

As used herein, “alkylcarboxy” refers to a group of the formula—C(═O)OR^(a) or —OC(═O)R^(a), wherein R^(a) is an alkyl group as definedherein. In certain embodiments, the alkyl of the alkylcarboxy group has1 to 6 carbon atoms (“C₁₋₆ alkylcarboxy”). In some embodiments, thealkyl of the alkylcarboxy group has 1 to 5 carbon atoms (“C₁₋₅alkylcarboxy”). In some embodiments, the alkyl of the alkylcarboxy grouphas 1 to 4 carbon atoms (“C₁₋₄ alkylcarboxy”). In some embodiments, thealkyl of the alkylcarboxy group has 1 to 3 carbon atoms (“C₁₋₃alkylcarboxy”). In some embodiments, the alkyl of the alkylcarboxy grouphas 1 to 2 carbon atoms (“C₁₋₂ alkylcarboxy”). Unless otherwisespecified, each instance of the alkyl of the alkylcarboxy group isindependently unsubstituted (“unsubstituted alkylcarboxy”) orsubstituted (“substituted alkylcarboxy”) with one or more substituents.In certain embodiments, the alkylcarboxy group is an unsubstituted C₁₋₆alkylcarboxy. In certain embodiments, the alkylcarboxy group is asubstituted C₁₋₆ alkylcarboxy.

As used herein, alone or as part of another group, “alkenyl” refers to aradical of a straight-chain or branched hydrocarbon group having from 2to 30 carbon atoms and one or more carbon-carbon double bonds (“C₂₋₃₀alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbonatoms (“C₂₋₂₀ alkenyl”). In some embodiments, an alkenyl group has 2 to20 carbon atoms (“C₂₋₁₀ alkenyl”). In some embodiments, an alkenyl grouphas 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄) and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Unless otherwise specified, each instance of an alkenyl group isindependently unsubstituted (an “unsubstituted alkenyl”) or substituted(a “substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is an unsubstituted C₂₋₆ alkenyl. Incertain embodiments, the alkenyl group is a substituted C₂₋₆ alkenyl.

As used herein, alone or as part of another group, “alkynyl” refers to aradical of a straight-chain or branched hydrocarbon group having from 2to 30 carbon atoms and one or more carbon-carbon triple bonds (“C₂₋₃₀alkynyl”). In some embodiments, an alkynyl group has 2 to 20 carbonatoms (“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to10 carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has two carbon atom(“C₂ alkynyl”). The one or more carbon-carbon triple bonds can beinternal (such as in 2-butynyl) or terminal (such as in 1-butynyl).Examples of C₂₋₄ alkynyl groups include, without limitation, ethynyl(C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄)and the like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆) and the like.Unless otherwise specified, each instance of an alkynyl group isindependently unsubstituted (“unsubstituted alkynyl”) or substituted(“substituted alkynyl”) with one or more substituents. In certainembodiments, the alkynyl group is an unsubstituted C₂₋₆ alkynyl. Incertain embodiments, the alkynyl group is a substituted C₂₋₆ alkynyl.

As used herein, a “saturated or unsaturated acyclic hydrocarbon” refersto radical of a saturated or unsaturated, straight-chain or branched,hydrocarbon group having from 1 to 20 carbon atoms and optionally one ormore carbon-carbon double or triple bonds. In certain embodiments, thehydrocarbon group is saturated. In some embodiments, the hydrocarbongroup is unsaturated, and contains one or more carbon-carbon double ortriple bonds. In some embodiments, the hydrocarbon group contains 1-10carbon atoms. In certain embodiments, the hydrocarbon group contains 1-5carbon atoms. In some embodiments, the hydrocarbon group contains 1-4carbon atoms. In some embodiments, the hydrocarbon group contains 1-3carbon atoms. In some embodiments, the hydrocarbon group contains 1-2carbon atoms.

As used herein, “carbocyclyl” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 7 ring carbon atoms (“C₃₋₇carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms(“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Exemplary C₃₋₇ carbocyclylgroups include, without limitation, cyclopropyl (C₃), cyclopropenyl(C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅),cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl(C₆), cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇),cycloheptatrienyl (C₇), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing afused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”)) and can be saturated or can contain one or morecarbon-carbon double or triple bonds. “Carbocyclyl” also includes ringsystems wherein the carbocyclyl ring, as defined above, is fused withone or more aryl or heteroaryl groups wherein the point of attachment ison the carbocyclyl ring, and in such instances, the number of carbonscontinue to designate the number of carbons in the carbocyclic ringsystem. Unless otherwise specified, each instance of a carbocyclyl groupis independently unsubstituted (“unsubstituted carbocyclyl”) orsubstituted (“substituted carbocyclyl”) with 1, 2, 3, 4, or 5substituents as described herein. In certain embodiments, thecarbocyclyl group is an unsubstituted C₃₋₁₀ carbocyclyl. In certainembodiments, the carbocyclyl group is a substituted C₃₋₁₀ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 7 ring carbon atoms (“C₃₋₇cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 5 to 6 ring carbon atoms (“C₅₋₆ cycloalkyl”). Examples of C₅₋₆cycloalkyl groups include cyclopentyl (C₅) and cyclohexyl (C₅). Examplesof C₃₋₆ cycloalkyl groups include the aforementioned C₅₋₆ cycloalkylgroups as well as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₇cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇). Unless otherwise specified, each instance of acycloalkyl group is independently unsubstituted (“unsubstitutedcycloalkyl”) or substituted (“substituted cycloalkyl”) with one or moresubstituents. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₇ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₇ cycloalkyl.

As used herein, alone or as part of another group, “heterocyclyl” refersto a radical of a 3- to 8-membered non-aromatic ring system having ringcarbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen and sulfur (“3-8 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic heterocyclyl”)),and can be saturated or can contain one or more carbon-carbon double ortriple bonds. Heterocyclyl polycyclic ring systems can include one ormore heteroatoms in one or both rings. “Heterocyclyl” also includes ringsystems wherein the heterocycyl ring, as defined above, is fused withone or more carbocycyl groups wherein the point of attachment is eitheron the carbocycyl or heterocyclyl ring, or ring systems wherein theheterocyclyl ring, as defined above, is fused with one or more aryl orheteroaryl groups, wherein the point of attachment is on theheterocyclyl ring, and in such instances, the number of ring memberscontinue to designate the number of ring members in the heterocyclylring system.

In some embodiments, a heterocyclyl group is a 5-8 membered non-aromaticring system having ring carbon atoms and 1-4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen andsulfur (“5-8 membered heterocyclyl”). In some embodiments, aheterocyclyl group is a 5-6 membered non-aromatic ring system havingring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen and sulfur (“5-6 memberedheterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In someembodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatomsselected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1 ring heteroatom selected from nitrogen,oxygen and sulfur. Exemplary 3-membered heterocyclyls containing 1heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.Exemplary 4-membered heterocyclyls containing 1 heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyls containing 1 heteroatom include, withoutlimitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclyls containing 2 heteroatoms include,without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary5-membered heterocyclyls containing 3 heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing 1 heteroatom include, withoutlimitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, andthianyl. Exemplary 6-membered heterocyclyl groups containing 2heteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing2 heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing 1 heteroatom include, withoutlimitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,azocanyl, oxecanyl and thiocanyl. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (“unsubstitutedheterocyclyl”) or substituted (“substituted heterocyclyl”) with one ormore substituents. In certain embodiments, the heterocyclyl group is anunsubstituted 3-8 membered heterocyclyl. In certain embodiments, theheterocyclyl group is a substituted 3-8 membered heterocyclyl.

As used herein, alone or as part of another group, “aryl” refers to aradical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2aromatic ring system having 6-10 ring carbon atoms and zero heteroatomsprovided in the aromatic ring system (“C₆₋₁₀ aryl”). In someembodiments, an aryl group has 6 ring carbon atoms (“C₆ aryl”; e.g.,phenyl). In some embodiments, an aryl group has 10 ring carbon atoms(“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). “Aryl”also includes ring systems wherein the aryl ring, as defined above, isfused with one or more cycloalkyl or heterocyclyl groups wherein theradical or point of attachment is on the aryl ring, and in suchinstances, the number of carbon atoms continue to designate the numberof carbon atoms in the aryl ring system. Unless otherwise specified,each instance of an aryl group is independently unsubstituted (an“unsubstituted aryl”) or substituted (a “substituted aryl”) with one ormore substituents as described herein. In certain embodiments, the arylgroup is an unsubstituted C₆₋₁₀ aryl. In certain embodiments, the arylgroup is a substituted C₆₋₁₀ aryl.

As used herein, alone or as part of another group, “heteroaryl” refersto a radical of a 5-14 membered monocyclic or polycyclic (e.g.,bicyclic) 4n+2 aromatic ring system having 4-10 ring carbon atoms and1-4 ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl polycyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocycyl or heterocycyl groups wherein the point of attachmentis on the heteroaryl ring, and in such instances, the number of ringmembers continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl or on theheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused polycyclic(aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein onering does not contain a heteroatom (e.g., indolyl, quinolinyl,carbazolyl and the like) the point of attachment can be on either ring,i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ringthat does not contain a heteroatom (e.g., 5-indolyl). In someembodiments, a heteroaryl group is a 5-10 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen and sulfur. Exemplary5-membered heteroaryls containing 1 heteroatom include, withoutlimitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-memberedheteroaryls containing 2 heteroatoms include, without limitation,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryls containing 3 heteroatomsinclude, without limitation, triazolyl, oxadiazolyl, thiadiazolyl.Exemplary 5-membered heteroaryls containing 4 heteroatoms include,without limitation, tetrazolyl. Exemplary 6-membered heteroarylscontaining 1 heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryls containing 2 heteroatoms include,without limitation, pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary6-membered heteroaryls containing 3 or 4 heteroatoms include, withoutlimitation, triazinyl and tetrazinyl, respectively. Exemplary 7 memberedheteroaryls containing 1 heteroatom include, without limitation,azepinyl, oxepinyl and thiepinyl. Exemplary 5,6-bicyclic heteroarylsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include,without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.Unless otherwise specified, each instance of a heteroaryl group isindependently unsubstituted (an “unsubstituted heteroaryl”) orsubstituted (a “substituted heteroaryl”) with one or more substituents.In certain embodiments, the heteroaryl group is an unsubstituted 5-10membered heteroaryl. In certain embodiments, the heteroaryl group is asubstituted 5-10 membered heteroaryl.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl,referred to without the suffix “-ene,” describe a monoradical of alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl,respectively, and as defined herein, wherein the monoradical is attachedto another group by only one single bond. Groups referred to with thesuffix “-ene”, such as alkylene, alkenylene, alkynylene, carbocyclylene,heterocyclylene, arylene and heteroarylene groups, describe a diradicalof alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl, respectively, and as defined herein, wherein the diradicalis attached to one or two groups by two single bonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom etc.)is replaced with a permissible substituent, e.g., a substituent whichupon substitution results in a stable compound, e.g., a compound whichdoes not spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group (e.g., 1, 2, 3, 4 or 5 positions), and when morethan one position in any given structure is substituted, the substituentis either the same or different at each position. The term “substituted”is contemplated to include substitution with all permissiblesubstituents of organic compounds, any of the substituents describedherein that results in the formation of a stable compound. The presentinvention contemplates any and all such combinations in order to arriveat a stable compound. For purposes of this invention, heteroatoms suchas nitrogen may have hydrogen substituents and/or any suitablesubstituent as described herein which satisfy the valencies of theheteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(OR^(cc))R^(bb), —SH, —SR^(aa), —SSR^(cc), —C(═O)R^(aa),—CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa), —OC(═O)R^(aa), —OCO₂R^(aa),—C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂, —NR^(bb)C(═O)R^(aa),—NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa),—P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂,—P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂,—OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8 membered heterocyclyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8 membered heterocyclyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl, or two R^(aa) groups arejoined to form a 3-8 membered heterocyclyl or 5-10 membered heteroarylring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇carbocyclyl, 3-8 membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-8 memberedheterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8 memberedheterocyclyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, or two R^(cc)groups are joined to form a 3-8 membered heterocyclyl or 5-10 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee), —C(═O)R^(ee), —CO₂H,—CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee), —C(═O)N(R^(ff))₂,—OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee), NR^(ff)CO₂R^(ee),—NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee),—OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,—NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,—SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,—OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),—SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,—OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇carbocyclyl, 3-8 membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd)substituents can bejoined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8 membered heterocyclyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8 memberedheterocyclyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, or two R^(ff)groups are joined to form a 3-8 membered heterocyclyl or 5-10 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl),—OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂,—OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),—OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl),—C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8 memberedheterocyclyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; or two geminalR^(gg) substituents can be joined to form ═O or ═S.

As used herein, the term “halo” or “halogen” refers to fluorine (fluoro,—F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

As used herein, “nitro” refers to the group —NO₂.

As used herein, “oxo” refers to the group ═O.

As used herein, “hydroxyl” or “hydroxy” refers to the group —OH. Theterm “substituted hydroxyl” or “substituted hydroxy,” by extension,refers to a hydroxyl group wherein the oxygen atom is substituted with agroup other than hydrogen, e.g., selected from —OR^(aa), —ON(R^(bb))₂,—OC(═O)R^(aa), —OC(═O)SR^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂,—OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂,—OS(═O)R^(aa), —OSO₂R^(aa), —OSi(R^(aa))₃, —OP(R^(cc))₂, —OP(R^(cc))₃,—OP(═O)₂R^(aa), —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂,and —OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein.

As used herein, the term “thiol” or “thio” refers to the group —SH. Theterm “substituted thiol” or “substituted thio,” by extension, refers toa thiol group wherein the sulfur atom is substituted with a group otherthan hydrogen, and includes groups selected from —SR^(aa), —S═SR^(cc),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —SC(═O)OR^(aa), and —SC(═O)R^(aa),wherein R^(aa)and R^(cc) are as defined herein.

As used herein, the term, “amino” refers to the group —NH₂. As usedherein, the term “substituted amino” refers to a monosubstituted,disubstituted, or trisubstituted amino group, as defined herein.

As used herein, the term “monosubstituted amino” refers to an aminogroup substituted with one hydrogen and one group other than hydrogen,and includes groups selected from —NH(R^(bb)), —NHC(═O)R^(aa),—NHCO₂R^(aa), —NHC(═O)N(R^(bb))₂, —NHC(═NR^(bb))N(R^(bb))₂,—NHSO₂R^(aa), —NHP(═O)(OR^(cc))₂, and —NHP(═O)(NR^(bb))₂, whereinR^(aa), R^(bb) and R^(cc) are as defined herein, and wherein R^(bb) ofthe group —NH(R^(bb)) is not hydrogen.

As used herein, the term “disubstituted amino” refers to an amino groupsubstituted with two groups other than hydrogen, and includes groupsselected from —N(R^(bb))₂, —NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa),—NR^(bb)C(═O)N(R^(bb))₂, —NR^(bb)C(═NR^(bb))N(R^(bb))₂,—NR^(bb)SO₂R^(aa), —NR^(bb)P(═O)(OR^(cc))₂, and —NR^(bb)P(═O)(NR^(bb))₂,wherein R^(aa), R^(bb), and R^(cc) are as defined herein, with theproviso that the nitrogen atom directly attached to the parent moleculeis not substituted with hydrogen.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, 3-8 memberedheterocyclyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, or two R^(cc)groups attached to an N atom are joined to form a 3-8 memberedheterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined above.

In certain embodiments, the substituent present on the nitrogen atom isan “amino protecting group”. Amino protecting groups include, but arenot limited to, —OH, —OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),C₁₋₁₀ alkyl (e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined herein. Aminoprotecting groups are well known in the art and include those describedin detail in Protecting Groups in Organic Synthesis, T. W. Greene and P.G. M. Wuts, ^(3rd) edition, John Wiley & Sons, 1999, incorporated hereinby reference.

For example, amino protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxycarbonylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Amino protecting groups such as carbamate groups (e.g., —C(═O)OR^(aa))include, but are not limited to, methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Amino protecting groups such as sulfonamide groups (e.g., —S(═O)₂R^(aa))include, but are not limited to, p-toluenesulfonamide (Ts),benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other amino protecting groups include, but are not limited to,phenothiazinyl-(10)-carbonyl derivative,N′-p-toluenesulfonylaminocarbonyl derivative, N′-phenylaminothiocarbonylderivative, N-benzoylphenylalanyl derivative, N-acetylmethioninederivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide,N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct (STABASE), 5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N-(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copperchelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on the oxygen atom is an“oxygen protecting group”. Oxygen protecting groups include, but are notlimited to —R^(aa), —N(R^(bb))₂, —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, the entirety of which isincorporated herein by reference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethylcarbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc),isobutyl carbonate, vinyl carbonate, allyl carbonate, p-nitrophenylcarbonate, benzyl carbonate, p-methoxybenzyl carbonate,3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzylcarbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate,methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxycarbonyl)benzoate, α-naphthoate,N,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate,dimethylphosphinothioyl, 2,4-dinitrophenylsulfenate, sulfate,methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). Forprotecting 1,2- or 1,3-diols, the protecting groups include methyleneacetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylideneketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylideneacetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal,cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal,2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal,2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethyleneacetal, dimethoxymethylene ortho ester, 1-methoxyethylidene ortho ester,1-ethoxyethylidine ortho ester, 1,2-dimethoxyethylidene ortho ester,a-methoxybenzylidene ortho ester, 1-(N,N-dimethylamino)ethylidenederivative, α-(N,N′-dimethylamino)benzylidene derivative,2-oxacyclopentylidene ortho ester, di-t-butylsilylene group (DTBS),1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS),tetra-t-butoxydisiloxane-1,3-diylidene derivative (TBDS), cycliccarbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

These and other exemplary substituents are described in more detail inthe Detailed Description, the Examples and in the Claims. The inventionis not intended to be limited in any manner by the above exemplarylisting of substituents.

Other definitions

As used herein, the terms “salt”, “acceptable salt”, or“pharmaceutically acceptable salt” refer to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, S. M. Berge et al., describepharmaceutically acceptable salts in detail in J. PharmaceuticalSciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of thecompounds of this invention include those derived from suitableinorganic and organic acids and bases. Examples of pharmaceuticallyacceptable, nontoxic acid addition salts are salts of an amino groupformed with inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citricacid, succinic acid or malonic acid or by using other methods used inthe art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

As used herein, the term “prodrug” means a biologically activederivative of a compound that can hydrolyze, oxidize, or otherwise reactunder biological conditions (in vitro or in vivo) to provide thepharmacologically active compound. In this instance, the “prodrug” is acompound administered to a subject, and the pharmacologically activecompound is the “active metabolite thereof.” In certain cases, a prodrughas improved physical and/or delivery properties over the parentcompound. Prodrugs are typically designed to enhance pharmaceuticallyand/or pharmacokinetically based properties associated with the parentcompound. The advantage of a prodrug can lie in its physical properties,such as enhanced water solubility for parenteral administration atphysiological pH compared to the parent compound, or it enhancesabsorption from across the skin, or it may enhance drug stability forlong-term storage.

“Metabolic syndrome” is a combination of medical disorders that, whenoccurring together, increases the risk of developing cardiovasculardisease and diabetes. A recent joint scientific statement (Alberti,supra) requires the presence at least 3 of the following 5 findings:elevated waist circumference (definition varies by country), elevatedtriglycerides (greater than or equal to 150 mg/dL), reduced HDL (under40 mg/dL in males or under 50 mg/dL in females), elevated blood pressure(systolic greater than or equal to 130 mm and/or diastolic greater thanor equal to 85 mm Hg), and elevated fasting glucose (greater than orequal to 100 mg/dL). Principal disorders associated with or used in thediagnosis of metabolic syndrome include, but are not limited to,obesity, dyslipidemia, and diabetic conditions, and conditionsassociated with these disorders, such as elevated glucose levels andhypertension.

As used herein, an “individual” or “subject” to which administration iscontemplated includes, but is not limited to, humans (i.e., a male orfemale of any age group, e.g., a pediatric subject (e.g., child,adolescent) or adult subject (e.g., young adult, middle-aged adult orsenior adult)), other primates (e.g., cynomolgus monkeys, rhesusmonkeys) and commercially relevant mammals such as cattle, pigs, horses,sheep, goats, cats, and/or dogs. In any aspect and/or embodiment of theinvention, the subject is a human subject.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” “an amount sufficient” or “sufficient amount” of acompound means the level, amount or concentration of the compound neededto treat or prevent metabolic syndrome and/or a disorder associated withmetabolic syndrome, or to treat or prevent a particular parameter (e.g.,body weight, body fat, adipocytes, lipid or glucose concentrations inthe blood) in the body of a subject, without causing significantnegative or adverse side effects to body or the treated tissue. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of metabolicsyndrome and/or a disorder associated with metabolic syndrome, orenhances the therapeutic efficacy of another therapeutically activeagent.

As used herein, a “therapeutically effective concentration” refers tothe concentration (e.g., μg/mL) of a compound, or active metabolitethereof, in the blood of a subject within the therapeutic range. The“therapeutic range” refers to the concentration above the minimaleffective concentration (i.e., the required level of a compound neededfor therapeutic effect) and below the minimum effective concentrationfor adverse effects (i.e., the toxic level of the compound).

As used herein, the terms “reduce”, “reduction”, “reducing”, “lower”, or“lowering” means to diminish or lessen the volume, size, mass, bulk,density, amount, and/or quantity of a substance (e.g., body weight, bodyfat, adipocyte size, adipocyte number, adipose tissue volume, adiposetissue thickness, lipid concentration, glucose concentration) in thebody of a subject.

As used herein, the term “eliminate” means to completely remove anyunwanted or undesired volume, size, mass, bulk, density, amount, and/orquantity of a substance (e.g., excess body weight, excess body fat,excess adipocytes, excess adipose tissue, elevated lipid concentration,elevated glucose concentration) in the body of a subject.

As used herein, “suffer”, “suffers” or “suffering from” refers to asubject having metabolic syndrome and/or a disorder associated withmetabolic syndrome. As used herein, “likely to suffer” refers to asubject who has not been diagnosed with metabolic syndrome and/or adisorder associated with metabolic syndrome by a medical practitioner,but has a predisposition (e.g., genetic and/or physiologicpredisposition), or exhibits signs or symptoms of metabolic syndromeand/or a disorder associated with metabolic syndrome.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from metabolic syndrome and/or a disorderassociated with metabolic syndrome, which reduces the severity of themetabolic syndrome and/or a disorder associated with metabolic syndrome,or retards or slows the progression of metabolic syndrome and/or adisorder associated with metabolic syndrome.

As used herein, unless otherwise specified, the terms “prevent,”“preventing” and “prevention” contemplate an action that occurs before asubject begins to suffer from metabolic syndrome and/or a disorderassociated with metabolic syndrome, which inhibits or reduces theseverity of the metabolic syndrome and/or a disorder associated withmetabolic syndrome.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a randomized, controlled, repeat-dose, 4-week trialconducted on (db−/db−) mice, which are defective for the leptin receptor(Jackson Laboratories). These mice are genetically obese, dyslipidemic,and diabetic. Mice were obtained from Jackson Laboratories andacclimated to the facility. At about 5 weeks of age, mice wereprospectively randomized into groups and assigned to the treatmentconditions shown in FIG. 1. Topical treatments were applied in a thinfilm to the right flank skin without occlusive dressings; subcutaneousinjections were also administered to the right flank. Mice were observedfor condition and weighed daily. They were housed in the same room, in11 cages according to group, and fed ad libitum. Skin tissue was sampledand serum lipids tested on day 28. Tissue was fixed in formalin andstained with hematoxylin and eosin.

FIG. 2 shows mean weight gain of the mice treated in FIG. 1 for days 0to 28, by group. Animals treated with vehicle only (Groups 1 and 2)showed an expected amount of weight gain for the strain (normative data,Jackson Laboratories). Transdermal bimatoprost isopropyl ester (BIE) andbimatoprost free acid (BFA) reduced weight gain significantly and in adose-dependent manner, but topical bimatoprost did not. SubcutaneousBIE, subcutaneous BFA, and intraperitoneal BFA had no significant effecton weight gain.

FIG. 3 shows representative histologic sections of skin and subcutaneousfat from untreated (left) and treated (right) flanks of animals assignedto vehicle only (Group 1), topical bimatoprost 0.3% (Group 4), andtopical BIE 0.3% (Group 11). All sections are shown at the samemagnification (scale bar at top right=640 microns). The surface of theskin is oriented toward the top and left of each panel. Arrows in eachsection denote the panniculus carnosus, an anatomic layer that separatesthe first layer of subdermal fat from deeper, subpannicular fat(separation artifact is commonly seen deep to the panniculus and is notan in vivo process).

FIG. 4 shows mean, unfasted, serum lipid concentrations for each group(day 28), expressed as a percent reduction relative to control (Group1).

FIG. 5 charts the triglyceride and total cholesterol results (mg/dl) forthe topical treatment conditions of FIG. 4 as follows: Group 1=C, 3=D,4=E, 5=F, 6=G, 10=H, 11=I.

FIG. 6 depicts a controlled, repeat-dose, 4-week, dose-ranging study oflatanoprost transdermal cream was conducted in Zucker Diabetic Fatty(ZDF) rats (ZDF-Lepr^(fa)/Crl), which are defective for the leptinreceptor, obese, hyperlipidemic, and diabetic. Male ZDF rats,approximately 8 weeks old, were obtained from Jackson Laboratories andacclimated to the facility. They were prospectively assigned totreatment conditions shown in FIG. 6. There were 3 animals per treatmentarm. Test articles were applied in a thin film to the right flankwithout occlusive dressings, at 0.3 ml daily for 28 days. Rats were fedad libitum and housed in the same room in 4 cages according to group.They were observed for condition and weighed daily. Food consumption wasmeasured by residual weight of chow. Animals were fasted overnight priorto day 29, and Oral Glucose Tolerance Tests were conducted on day 29 (1g glucose per kg body weight). Skin tissue and serum chemistries werecollected at day 29.

FIG. 7 depicts shows mean weight gain, by group, for days 0 to 29.Compared to vehicle, topical latanoprost 0.5%, 0.05%, 0.005% caused adose-dependent reductions in weight gain, which were statisticallysignificant for the 0.5% and 0.05% concentrations.

FIG. 8 shows representative histologic sections of skin and subcutaneousfat from untreated (left) and treated (right) flanks of animals assignedto vehicle only (Group 1), latanoprost 0.005% (Group 2), and latanoprost0.5% (Group 4). All sections are shown at the same magnification (scalebar at top right=500 microns). The surface of the skin is orientedtoward the top of each panel.

FIG. 9 summarizes serum lipid levels by group, as measured on day 29.Compared to vehicle-treated control animals, latanoprost was associatedwith dose-dependent reductions in triglycerides and LDL, anddose-dependent increases in HDL and HDL:LDL ratio. These benefits wereseen at the 0.5% and 0.05% concentrations, and were absent at the 0.005%concentration. Because of the small sample size, these differences didnot reach statistical significance, except for the HDL:LDL ratio ofLatanoprost 0.5% vs. vehicle (one-sided p<0.05).

FIG. 10 shows the results of oral glucose tolerance testing on day 29.Latanoprost caused dose-dependent improvements in oral glucosetolerance, seen at the 0.5% and 0.05% concentration.

FIG. 11 indicates the serum glucose Area Under the Curve from 15 to 120minutes post-glucose load (AUC₁₅₋₁₂₀) was 12% and 26% lower in animalstreated with latanoprost 0.05% and 0.5%, respectively, compared tovehicle-treated animals. There was no effect on oral glucose tolerancewith latanoprost 0.005%.

FIG. 12 compares various topical doses of latanoprost in mouse, rat, andhuman, with respect to projected systemic dose.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present invention describes uses of certain prostaglandins, i.e.,one or more compounds of compounds of Formula (I) or (II), or apharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof, as described herein, to reduce, or eliminate altogether, bodyfat, for example, adipose tissue and/or adipocytes, in a subject, forexample, a human. The invention further relates to uses of saidcompounds to reduce the concentration of lipid (e.g., triglycerides,cholesterol, lipoproteins (e.g., low density lipoprotein and very lowdensity lipoprotein)), and/or increase HDL, in the blood of a subject.

Previously members of the genus of F-series prostaglandins wererecognized as hypotensive agents. For example, see U.S. Pat. Nos.5,688,819 and 6,403,649, incorporated herein by reference. Thesecompounds were shown to effect vasodilation and thereby were predictedto relieve symptoms of various diseases associated with increased bloodpressure, including acute myocardial infarction, vascular thrombosis,hypertension, pulmonary hypertension, ischemic heart disease, congestiveheat failure, and angina pectoris. These compounds were also shown to beeffective ocular hypotensive agents useful for the treatment of elevatedintraocular pressure, for example, glaucoma.

Previous studies have shown that the use of bimatoprost eyedrops for thetreatment of glaucoma does decrease intraocular pressure, but alsoinduces unwanted side effects, which were eventually understood to bedue to the atrophy of the fat normally present around the eye, i.e., theorbital fat. The use of bimatoprost to reduce unwanted fat by localadministration was disclosed in U.S. Pat. No. 7,666,912, incorporatedherein by reference.

The present invention arises in part from a new finding thatadministration of certain F-series prostaglandins to obese,dyslipidemic, and/or diabetic animals has beneficial effects ondisorders associated with metabolic syndromes in these animals. Theobserved effects include reduced obesity, reduced weight gain, reduceserum triglycerides, reduced serum LDL, increased serum HDL, reducedserum glucose, and/or improved glucose tolerance.

The present invention also arises from the observation that systemicadministration of certain F-series prostaglandins to obese animalsreduces weight and/or weight gain in those animals.

The present invention also arises from the experimental identificationof certain preferred species from among the genus of F-seriesprostaglandins for the purposes of the invention.

Prior to this work, it was envisioned that bimatoprost, whennon-systemically and locally administered topically, subcutaneously,intramuscularly, or intralesionally at certain concentrations, e.g.,0.003%, 0.03%, or 0.3%, would locally reduce fat in a subject at thesite of administration. See, e.g., the Examples of U.S. Pat. No.7,666,912, incorporated herein by reference. In a human, an overall doseof 30 mg/m²/d (about 57 mg) using 0.3% ointment would involveapplication of about 20 g of ointment daily. The inventor has nowdiscovered that while 0.3% topical bimatoprost (at an overall dose ofabout 30 mg/m²/d) locally reduces subcutaneous fat in a subject, theisopropyl ester and free acid of bimatoprost are significantly moreeffective in reducing subcutaneous fat. The inventor has furtherobserved that while topical administration of bimatoprost locallyreduces fat, topical administration of the isopropyl ester and free acidof bimatoprost reduces fat not only locally but also throughout thebody, indicative of a systemic effect. In fact, topical administrationof 0.3% bimatoprost isopropyl ester (at an overall dose of about 30mg/m²/d) shows a significant systemic effect in reduction of serumlipids in the bloodstream of a subject, while topical administration ofbimatoprost shows no systemic effect. See Example 1 below. The findingsand observations disclosed herein are indeed surprising and unexpected,especially considering U.S. Pat. No. 7,666,912 dissuades fromsystemically administering such compounds.

Furthermore, the inventor discovered that, unlike transdermaladministration of bimatoprost ester or the free acid, neithersubcutaneous nor intraperitoneal administration of bimatoprost ester orfree acid had any significant effect on fat reduction. Without wishingto be bound by any particular theory, the inventor postulates that evenif the compound is eliminated rapidly from the bloodstream (e.g.,latanoprost has a serum elimination half-life of about 17 minutes),transdermal administration may provide a depot effect whereby a compoundapplied to the skin may result in slow release of the active ingredientinto the bloodstream, and thereby result in a more sustainedtherapeutically effective concentration in the bloodstream. Furthermore,without wishing to be bound by theory, a similar effect can be obtained,for example, with a time release formulation, such as a controlled,extended, or sustained release formulation for oral, subcutaneous,intraperitoneal administration, or a continuous intravenous infusion,and the like.

Without wishing to be bound by any particular theory, reduction in fatas a function of administration of the compounds disclosed herein mayinclude reducing the number of fat cells (adipocytes), reducing thevolume of one or more fat cells (adipocytes), reducing maturation of oneor more fat cells (adipocytes), and/or dedifferentiating one or more fatcells (adipocytes). Such effects may be mediated through prostaglandinor prostaglandin-like receptors, and compounds according to theinvention may exert their effects as herein disclosed by acting asagonists at these receptors. Because adipocytes have been specificallyimplicated in a wide array of human diseases, the present inventionsuggests a means for treating and/or preventing adipocyte-relateddiseases, such as, but not limited to, metabolic syndrome, diabetes(e.g., type 2 diabetes), liver disease, atherosclerosis, fatty liver,hepatic fibrosis, inflammation or inflammatory disease, depression, anddementia. The invention can be used to reduce adipocytes byadministration of one or more of the compounds described herein, e.g.,one or more compounds of the Formula (I) or (II).

Thus, in one aspect, the present invention is directed to the use ofcertain prostaglandins, e.g., one or more compounds of the Formula (I)or (II), for treating and/or preventing metabolic syndrome or a disorderassociated with metabolic syndrome in the body of a subject, bysystemically administering the compound to the subject, e.g., at aconcentration sufficient to produce a systemic effect in the bloodstreamof a subject. More specifically a condition such as obesity,dyslipidemia, and/or a diabetic condition may be treated and/orprevented by administering to a subject a compound described herein.Furthermore, diseases and/or medical outcomes associated with themetabolic syndrome, obesity, dyslipidemia, and/or a diabetic conditionmay be treated and/or prevented by administering to a subject a compounddescribed herein.

The F-series prostaglandins disclosed herein are considered to bemembers of the class of prostaglandin F2α receptor agonists, which areknown to be in vitro inhibitors of adipocyte differentiation andsurvival. See, e.g., Serrero et al. (1992) Biochem. Biophys. Res.Commun. 183:438-442; Lepak et al. (1993) Prostaglandins 46:511-517;Serrero et al. (1995) Biochem. Biophys. Res. Commun. 212:1125-1132; andLepak et al. (1995) Endocrinology 136:3222-3229. Accordingly, withoutwishing to be bound by any particular theory, the fat-reducingproperties of these compounds may relate to its agonism of prostaglandinor prostaglandin-like receptors, in particular the prostaglandin FPreceptor (PTGFR).

Compounds for Use in the Present Invention

The present invention relates to uses of a compound of Formula (I) or(II), or a pharmaceutically acceptable salt, hydrate, solvate,stereoisomer, polymorph, tautomer, isotopically enriched derivative, orprodrug thereof.

In certain embodiments, the compound useful in the present invention isof Formula (I) or (II):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof;wherein:

L is a group of the formula

each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration;

A is optionally substituted C₁₋₁₀alkylene, optionally substitutedC₂₋₁₀alkenylene, or optionally substituted C₂₋₁₀ alkynylene, wherein thealkylene, alkenylene, or alkynylene group is optionally interrupted byone or more —O— or —S— groups;

B is hydrogen, optionally substituted C₃₋₇carbocyclyl, optionallysubstituted 3-8-membered-heterocyclyl, optionally substituted5-14-membered-heteroaryl, optionally substituted C₆₋₁₀aryl, optionallysubstituted C₁₋₃₀alkyl, optionally substituted C₂₋₃₀alkenyl, oroptionally substituted C₂₋₃₀alkynyl;

X is —OR₄, —SR₄, or —N(R₄)₂, wherein each instance of R₄ isindependently hydrogen, optionally substituted C₁₋₃₀alkyl, optionallysubstituted C₂₋₃₀alkenyl, optionally substituted C₂₋₃₀alkynyl, —C(═O)R₅,or —C(═O)OR₅, wherein R₅ is optionally substituted C₁₋₃₀alkyl,optionally substituted C₂₋₃₀alkenyl, or optionally substitutedC₂₋₃₀alkynyl, or two R₄ groups are joined to form an optionallysubstituted 3-8-membered-heterocyclyl or optionally substituted5-14-membered-heteroaryl ring;

Z is ═O, ═S, or ═NR_(Z), wherein R_(Z) is selected from hydrogen, anamino protecting group, —OH, substituted hydroxyl, optionallysubstituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇carbocyclyl,optionally substituted 3-8-membered-heterocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl, or Zrepresents two hydrogen atoms;

with regard to the compound of Formula (I), one of R₁ and R₂ is ═O, —OH,or a —O(CO)R₆ group and the other one is —OH or —O(CO)R₆, or R₁ is ═Oand R₂ is H, wherein R₆ is a an optionally substituted C₁₋₂₀alkyl,optionally substituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₇ wherein m is 0 or an integer of between 1-10,inclusive, and R₇ is optionally substituted C₃₋₇carbocyclyl, optionallysubstituted 3-8-membered-heterocyclyl, optionally substituted C₆₋₁₀aryl,or optionally substituted 5-14-membered-heteroaryl; and

with regard to the compound of Formula (II), R₁ is ═O, —OH, or —O(CO)R₆,wherein R₆ is a an optionally substituted C₁₋₂₀alkyl, optionallysubstituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, or—(CH₂)_(m)R₇ wherein m is 0 or an integer of between 1-10, inclusive,and R₇ is optionally substituted C₃₋₇carbocyclyl, optionally substituted3-8-membered-heterocyclyl, optionally substituted C₆₋₁₀aryl, oroptionally substituted 5-14-membered-heteroaryl.

In certain embodiments, the compound is not bimatoprost. In certainembodiments, the compound is not latanoprost. In certain embodiments,the compound is not travoprost.

In certain embodiments, the endocyclic dotted lines of Formula (I)(i.e., depicted in the 5-membered ring) each represent a single bond.

For example, in certain embodiments, wherein the endocyclic dotted linesof Formula (I) each represent a single bond, provided is a compoundhaving any one of the following stereochemistry:

pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof, wherein

, R₁, R₂, A, B, Z and X are as defined herein.

In certain embodiments, the exocyclic dotted line

(i.e., depicted outside of the 5-membered ring) of Formula (I) or (II)or a subset thereof represents a double bond in the cis or transconfiguration. In certain embodiments, the exocyclic dotted line

represents a double bond in the cis configuration.

In certain embodiments, each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration.

As generally defined above, one of R₁ and R₂ is ═O, —OH, or a —O(CO)R₆group and the other one is —OH or —O(CO)R₆, or R₁ is ═O and R₂ is H,wherein R₆ is an optionally substituted C₁₋₂₀alkyl, optionallysubstituted C₂₋₂₀alkenyl, optionally substituted C₂₋₂₀ alkynyl, or or—(CH₂)_(m)R₇ wherein m is 0 or an integer of between 1-10, inclusive,and R₇ is optionally substituted C₃₋₇carbocyclyl, optionally substituted3-8-membered-heterocyclyl, optionally substituted C₆₋₁₀aryl, oroptionally substituted 5-14-membered-heteroaryl.

In certain embodiments, R₁ is ═O and R₂ is H.

In certain embodiments, one of R₁ and R₂ is —OH, substituted hydroxyl,or —O(CO)R₃, and the other one is —OH, substituted hydroxyl, or—O(CO)R₆.

In certain embodiments, both R₁ and R₂ are —OH.

As generally defined above, A is optionally substituted C₁₋₁₀alkylene,optionally substituted C₂₋₁₀alkenylene or optionally substitutedC₂₋₁₀alkynylene, wherein the alkylene, alkenylene, or alkynylene groupis optionally interrupted by one or more —O— or —S— groups. As usedherein, “interrupted by” refers to an alkylene, alkenylene, oralkynylene which may optionally be flanked by an —O— or —S— group and/oran —O— or —S— group is included within the carbon chain.

In certain embodiments, A is optionally substituted C₁₋₁₀alkylene,optionally substituted C₂₋₁₀alkenylene or optionally substitutedC₂₋₁₀alkynylene, wherein the alkylene, alkenylene, or alkynylene groupis optionally interrupted by one —O— group.

In certain embodiments, A is optionally substituted C₄₋₆alkylene,optionally substituted C₄₋₆alkenylene or optionally substitutedC₄₋₆alkynylene, wherein the alkylene, alkenylene, or alkynylene group isoptionally interrupted by one —O— group.

In certain embodiments, A is optionally substituted C₄₋₆alkyleneoptionally interrupted by one —O— group. In certain embodiments, A isoptionally substituted C₄₋₆alkenylene optionally interrupted by one —O—group. In certain embodiments, A is optionally substitutedC₄₋₆alkynylene optionally interrupted by one —O— group.

In certain embodiments, A is optionally substituted C₁₋₁₀alkylene,optionally substituted C₂₋₁₀alkenylene or optionally substitutedC₂₋₁₀alkynylene, wherein the alkylene, alkenylene, or alkynylene groupis optionally interrupted by one —S— group.

In certain embodiments, A is optionally substituted C₄₋₆alkylene,optionally substituted C₄₋₆alkenylene or optionally substitutedC₄₋₆alkynylene, wherein the alkylene, alkenylene, or alkynylene group isoptionally interrupted by one —S— group.

In certain embodiments, A is optionally substituted C₄₋₆alkyleneoptionally interrupted by one —S— group. In certain embodiments, A isoptionally substituted C₄₋₆alkenylene optionally interrupted by one —S—group. In certain embodiments, A is optionally substitutedC₄₋₆alkynylene optionally interrupted by one —S— group.

In certain embodiments, A is substituted with one or more groupsselected from the group consisting of halogen, —OH, substitutedhydroxyl, or —O(CO)R₈, wherein R₈ is optionally substituted C₁₋₂₀alkyl,optionally substituted C₂₋₂₀alkenyl, optionally substitutedC₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 or an integer between 1-10,inclusive, and R₉ is optionally substituted C₃₋₇carbocyclyl, optionallysubstituted C₆₋₁₀aryl, and optionally substituted5-14-membered-heteroaryl.

In certain embodiments, A is substituted with ═O.

In certain embodiments, A is substituted with —OC(═O)R₈, wherein R₈ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉, wherein m is 0 oran integer between 1-10, inclusive, and R₉ is optionally substitutedC₃₋₇carbocyclyl, optionally substituted C₆₋₁₀aryl, or optionallysubstituted 5-14-membered-heteroaryl.

In certain embodiments, A is substituted with —OH or substitutedhydroxyl.

In certain embodiments, A is substituted with substituted hydroxyl.

In certain embodiments, A is substituted with —OH.

In certain embodiments, A is substituted with halogen, e.g., —F.

In certain embodiments, A is a group of the formula (i), (ii), (iii),(iv), (v), or (vi):

wherein each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration;

each instance of R₃ and R₃′ is hydrogen, halogen, —OH, substitutedhydroxyl, or —O(CO)R₈, wherein R₈ is optionally substituted C₁₋₂₀alkyl,optionally substituted C₂₋₂₀alkenyl, optionally substitutedC₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 or an integer between 1-10,inclusive, and R₉ is optionally substituted C₃₋₇carbocyclyl, optionallysubstituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl, or R₃ and R₃′ are joined to form ═O;

G is —O— or —S—;

y is 0, 1, or 2; and

x is 0 or 1.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments,

of formula (i), (ii), or (iii) represents a double bond in the cisconfiguration.

In certain embodiments,

of formula (i), (ii), or (iii) represents a double bond in the transconfiguration.

In certain embodiments, the group of the formula (i) is of the formula:

In certain embodiments, the group of the formula (ii) is of the formula:

In certain embodiments,

of formula (i), (ii), or (iii) represents a single bond.

In certain embodiments, the group of the formula (i) is of the formula:

In certain embodiments, the group of the formula (ii) is of the formula:

As generally defined above, each instance of R₃ and R₃′ is independentlyhydrogen, halogen, —OH, substituted hydroxyl, or —O(CO)R₈, wherein R₈ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 oran integer between 1-10, inclusive, and R₉ is optionally substitutedC₃₋₇carbocyclyl, optionally substituted C₆₋₁₀aryl, or optionallysubstituted 5-14-membered-heteroaryl; or R₃ and R₃′ are joined to form═O.

In certain embodiments, R₃ is hydrogen. In certain embodiments, R₃′ ishydrogen. In certain embodiments, R₃ is hydrogen and R₃′ is anon-hydrogen group. In certain embodiments, R₃′ is hydrogen and R₃ is anon-hydrogen group. In certain embodiments, however, neither R₃ nor R₃′is hydrogen.

In certain embodiments, R₃ and R₃′ are joined to form ═O.

In certain embodiments, R₃ and R₃′ are the same group. In certainembodiments, R₃ and R₃′ are different groups.

In certain embodiments, R₃ is —OH, substituted hydroxyl, or —O(CO)R₈,wherein R₈ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉wherein m is 0 or an integer between 1-10, inclusive, and R₉ isoptionally substituted C₃₋₇carbocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl. Incertain embodiments, R₃ is —O(CO)R₈. In certain embodiments, R₃ is —OHor substituted hydroxyl. In certain embodiments, R₃ is substitutedhydroxyl. In certain embodiments, R₃ is —OH.

In certain embodiments, R₃′ is —OH, substituted hydroxyl, or —O(CO)R₈,wherein R₈ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, optionally substituted C₂₋₂₀alkynyl, or —(CH₂)_(m)R₉wherein m is 0 or an integer between 1-10, inclusive, and R₉ isoptionally substituted C₃₋₇carbocyclyl, optionally substitutedC₆₋₁₀aryl, or optionally substituted 5-14-membered-heteroaryl. Incertain embodiments, R₃′ is —O(CO)R₈. In certain embodiments, R₃′ is —OHor substituted hydroxyl. In certain embodiments, R₃′ is substitutedhydroxyl. In certain embodiments, R₃′ is —OH.

In certain embodiments, R₃ is halogen, e.g., selected from fluoro,chloro, bromo, and iodo. In certain embodiments, R₃′ is halogen, e.g.,selected from fluoro, chloro, bromo, and iodo. In certain embodiments,R₃ is halogen and R₃′ is halogen, e.g., each independently selected fromfluoro, chloro, bromo, and iodo. In certain embodiments, both R₃ and R₃′are fluoro.

In certain embodiments, y is 0 and x is 1. In certain embodiments, y is0 and x is 0. In certain embodiments, y is 1 and x is 1. In certainembodiments, y is 1 and x is 0. In certain embodiments, y is 2 and x is0. In certain embodiments, y is 2 and x is 1.

As defined generally above, B is hydrogen, optionally substitutedC₃₋₇carbocyclyl, optionally substituted 3-8-membered-heterocyclyl,optionally substituted 5-14-membered-heteroaryl, optionally substitutedC₆₋₁₀aryl, optionally substituted C₁₋₃₀alkyl, optionally substitutedC₂₋₃₀alkenyl, or optionally substituted C₂₋₃₀alkynyl.

In certain embodiments, B is hydrogen.

In certain embodiments, B is optionally substituted C₁₋₃₀alkyl. Incertain embodiments, B is optionally substituted C₂₋₃₀alkenyl. Incertain embodiments, B is optionally substituted C₂₋₃₀alkynyl.

In certain embodiments, B is optionally substituted C₃₋₇carbocyclyl,e.g., optionally substituted cyclohexyl. In certain embodiments, B isoptionally substituted 3-8-membered-heterocyclyl. In certainembodiments, B is optionally substituted 5-14-membered-heteroaryl. Incertain embodiments, B is optionally substituted C₆₋₁₀aryl. In certainembodiments, B is optionally substituted C₆aryl (i.e., phenyl). Incertain embodiments, B is optionally substituted C₁₀aryl (i.e.,napthyl).

For example, in certain embodiments, B is an optionally substitutedphenyl of the formula (viii):

wherein:

Y is selected from the group consisting of optionally substitutedC₁₋₁₀alkyl, C₁₋₁₀perhaloalkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, halo, nitro, cyano, thiol,substituted thiol, hydroxyl, substituted hydroxyl, amino,monosubstituted amino, and disubstituted amino; and n is 0 or an integerof from 1 to 5, inclusive.

In certain embodiments, n is 0 or an integer from 1 to 3, inclusive.

-   In certain embodiments, n is 0 or an integer from 1 to 2, inclusive.-   In certain embodiments, n is 0. In certain embodiments, n is 1. In    certain embodiments, n is 2.-   In certain embodiments, n is 3.

For example, in certain embodiments, wherein n is 1, the group of theformula (viii) is of the formula:

In certain embodiments, wherein n is 2, the group of the formula (viii)is of the formula:

In certain embodiments, Y is halo, i.e. selected from fluoro, iodo,bromo, or chloro. In certain embodiments Y is chloro. In certainembodiments Y is fluoro.

In certain embodiments, Y is optionally substituted C₁₋₁₀alkyl orC₁₋₁₀perhaloalkyl.

In certain embodiments, Y is optionally substituted C₁₋₁₀alkyl. Incertain embodiments, Y is optionally substituted C₁₋₆alkyl. In certainembodiments, Y is optionally substituted C₁₋₄alkyl. In certainembodiments, Y is optionally substituted C₁₋₃alkyl. In certainembodiments, Y is optionally substituted C₁₋₂alkyl. In certainembodiments, Y is —CH₃, —CH₂F, or —CHF₂.

In certain embodiments, Y is C₁₋₁₀perhaloalkyl. In certain embodiments,Y is C₁₋₆perhaloalkyl. In certain embodiments, Y is C₁₋₄perhaloalkyl. Incertain embodiments, Y is C₁₋₃perhaloalkyl. In certain embodiments, Y isC₁₋₂perhaloalkyl. In certain embodiments, Y is —CF₃, —CF₂Cl, or —CFCl₂.

As generally defined above, Z is ═O, ═S, or ═NR_(Z), wherein R_(Z) isselected from hydrogen, an amino protecting group, —OH, substitutedhydroxyl, optionally substituted C₁₋₁₀alkyl, optionally substitutedC₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl, optionallysubstituted C₃₋₇carbocyclyl, optionally substituted3-8-membered-heterocyclyl, optionally substituted C₆₋₁₀aryl, oroptionally substituted 5-14-membered-heteroaryl, or Z represents twohydrogen atoms.

In certain embodiments, Z is ═O.

In certain embodiments, Z is ═S.

In certain embodiments, Z is ═NR_(Z), wherein R_(Z) is selected fromhydrogen, an amino protecting group, —OH, substituted hydroxyl,optionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, optionally substitutedC₃₋₇carbocyclyl, optionally substituted 3-8-membered-heterocyclyl,optionally substituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl. In certain embodiments, Z is ═NR_(Z) and R_(Z)is hydrogen.

In certain embodiments, Z represents two hydrogen atoms.

As generally defined above, X is —OR₄, —SR₄, or —N(R₄)₂, wherein eachinstance of R₄ is independently hydrogen, optionally substitutedC₁₋₃₀alkyl, optionally substituted C₂₋₃₀alkenyl, optionally substitutedC₂₋₃₀alkynyl, —C(═O)R₅, or —C(═O)OR₅, wherein R₅ is optionallysubstituted C₁₋₃₀alkyl, optionally substituted C₂₋₃₀alkenyl, oroptionally substituted C₂₋₃₀alkynyl, or two R₄ groups are joined to forman optionally substituted 3-8-membered-heterocyclyl or optionallysubstituted 5-14-membered-heteroaryl ring.

In certain embodiments, X is —OR₄. In certain embodiments, X is —OR₄,and R₄ is hydrogen. In certain embodiments, X is —OR₄, and R₄ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₄ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₄ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —OR₄, wherein R₄ is —C(═O)R₅, or —C(═O)OR₅.

In certain embodiments, X is —OR₄, and R₄ is —C(═O)R₅, and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄-alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₅ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —OR₄, and R₄ is —C(═O)OR₅ and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁alkyl, optionally substituted C₂₋₁₀alkenyl, oroptionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₅ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —SR₄. In certain embodiments, X is —SR₄,and R₄ is hydrogen. In certain embodiments, X is —SR₄, and R₄ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₄ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₄ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₄ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —SR₄, wherein R₄ is —C(═O)R₅, or —C(═O)OR₅.

In certain embodiments, X is —SR₄, and R₄ is —C(═O)R₅, and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₅ is optionally substituted C₂₋₆-alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —SR₄, and R₄ is —C(═O)OR₅ and R₅ isoptionally substituted C₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl,or optionally substituted C₂₋₂₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl,or optionally substituted C₂₋₁₀alkynyl. In certain embodiments, R₅ isoptionally substituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, orC₄₋₆alkyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl. In certainembodiments, R₅ is optionally substituted C₂₋₆alkynyl, e.g.,C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —N(R₄)₂. In certain embodiments, X is—N(R₄)₂ and at least one R₄ group is hydrogen. In certain embodiments, Xis —N(R₄)₂ and neither of the two R₄ groups are hydrogen. In certainembodiments, X is —N(R₄)₂ and at least one R₄ is optionally substitutedC₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl, or optionallysubstituted C₂₋₂₀alkynyl. In certain embodiments, X is —N(R₄)₂ and atleast one R₄ is optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₂₋₁₀alkenyl, or optionally substituted C₂₋₁₀alkynyl. Incertain embodiments, X is —N(R₄)₂ and at least one R₄ is optionallysubstituted C₁₋₆alkyl, e.g., C₁₋₃alkyl, C₃₋₄alkyl, or C₄₋₆alkyl Incertain embodiments, X is —N(R₄)₂ and at least one R₄ is optionallysubstituted C₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, or C₄₋₆alkenyl.In certain embodiments, X is —N(R₄)₂ and at least one R₄ is optionallysubstituted C₂₋₆alkynyl, e.g., C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.However, in certain embodiments, X is not —NH(iPr).

In certain embodiments, X is —N(R₄)₂ and at least one R₄ is —C(═O)R₅, or—C(═O)OR₅.

In certain embodiments, X is —N(R₄)₂ and at least one R₄ is —C(═O)R₅,and R₅ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, or optionally substituted C₂₋₂₀alkynyl. In certainembodiments, R₅ is optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₂₋₁₀alkenyl, or optionally substituted C₂₋₁₀alkynyl. Incertain embodiments, R₅ is optionally substituted C₁₋₆alkyl, e.g.,C₁₋₃alkyl, C₃₋₄alkyl, or C₄₋₆alkyl. In certain embodiments, R₅ isoptionally substituted C₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, orC₄₋₆alkenyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkynyl, e.g., C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In certain embodiments, X is —N(R₄)₂ and at least one R₄ is —C(═O)OR₅and R₅ is optionally substituted C₁₋₂₀alkyl, optionally substitutedC₂₋₂₀alkenyl, or optionally substituted C₂₋₂₀alkynyl. In certainembodiments, R₅ is optionally substituted C₁₋₁₀alkyl, optionallysubstituted C₂₋₁₀alkenyl, or optionally substituted C₂₋₁₀alkynyl. Incertain embodiments, R₅ is optionally substituted C₁₋₆alkyl, e.g.,C₁₋₃alkyl, C₃₋₄alkyl, or C₄₋₆alkyl. In certain embodiments, R₅ isoptionally substituted C₂₋₆alkenyl, e.g., C₂₋₃alkenyl, C₃₋₄alkenyl, orC₄₋₆alkenyl. In certain embodiments, R₅ is optionally substitutedC₂₋₆alkynyl, e.g., C₂₋₃alkynyl, C₃₋₄alkynyl, or C₄₋₆alkynyl.

In other embodiments, X is —N(R₄)₂ and the two R₄ groups are joined toform an optionally substituted 3-8-membered-heterocyclyl or optionallysubstituted 5-14-membered-heteroaryl ring.

In certain embodiments, wherein X is —OR₄, —SR₄, or —N(R₄)₂, any one ofR₄ or R₅ is optionally substituted C₁₋₃₀alkyl (e.g., C₁₋₁₀alkyl,C₁₋₆alkyl, C₁₋₃alkyl, C₇₋₃₀alkyl, C₁₀₋₃₀alkyl, C₇₋₂₅alkyl, C₁₀₋₂₅alkyl,C₁₅₋₂₅alkyl). In certain embodiments, any one of R₄ or R₅ is optionallysubstituted C₂₋₃₀alkenyl (e.g., C₂₋₁₀alkenyl, C₂₋₆alkenyl, C₁₋₃alkenyl,C₇₋₃₀alkenyl, C₁₀₋₃₀alkenyl, C₇₋₂₅alkenyl, C₁₀₋₂₅alkenyl,C₁₅₋₂₅alkenyl). In certain embodiments, any one of R₄ or R₅ isoptionally substituted C₂₋₃₀alkynyl (e.g., C₂₋₁₀alkynyl, C₂₋₆alkynyl,C₁₋₃alkynyl, C₇₋₃₀alkynyl, C₁₀₋₃₀alkynyl, C₇₋₂₅alkynyl, C₁₀₋₂₅alkynyl,C₁₅₋₂₅alkynyl).

In any of the above embodiments, when R₄ or R₅ are defined as aC₇₋₃₀alkyl or C₇₋₃₀alkenyl groups, such groups may also be referred toas “lipid tails.” Lipid tails present in these lipid groups can besaturated and unsaturated, depending on whether or not the lipid tailcomprises double bonds. The lipid tail can also comprise differentlengths, often categorized as medium (i.e., with tails between 7-12carbons, e.g., C₇₋₁₂ alkyl or C₇₋₁₂ alkenyl), long (i.e., with tailsgreater than 12 carbons and up to 22 carbons, e.g., C₁₃₋₂₂ alkyl orC₁₃₋₂₂ alkenyl), or very long (i.e., with tails greater than 22 carbons,e.g., C₂₃₋₃₀ alkyl or C₂₃₋₃₀ alkenyl).

Exemplary unsaturated lipid tails include, but are not limited to:

Myristoleic —(CH₂)₇CH═CH(CH₂)₃CH₃, Palmitoliec —(CH₂)₇CH═CH(CH₂)₅CH₃,Sapienic —(CH₂)₄CH═CH(CH₂)₈CH₃, Oleic —(CH₂)₇CH═CH(CH₂)₇CH₃, Linoleic—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃, α-Linolenic—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃, Arachinodonic—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃, Eicosapentaenoic—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃, Erucic—(CH₂)₁₁CH═CH(CH₂)₇CH₃, and Docosahexaenoic—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH—CH₂CH₃.

Exemplary saturated lipid tails include, but are not limited to:

Lauric —(CH₂)₁₀CH₃, Myristic —(CH₂)₁₂CH₃, Palmitic —(CH₂)₁₄CH₃, Stearic—(CH₂)₁₆CH₃, Arachidic —(CH₂)₁₈CH₃, Behenic —(CH₂)₂₀CH₃, Lignoceric—(CH₂)₂₂CH₃, and Cerotic —(CH₂)₂₄CH₃.

In certain embodiments of Formula (I), the compound is of Formula (I-a):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein;

each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration;

each instance of R₃ and R₃′ is independently hydrogen, halogen, —OH,substituted hydroxyl, or —O(CO)R₈, wherein R₈ is optionally substitutedC₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substitutedC₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 or an integer between 1-10,inclusive, and R₉ is optionally substituted C₃₋₇carbocyclyl, optionallysubstituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl, or R₃ and R₃′ are joined to form ═O;

Y is selected from the group consisting of optionally substitutedC₁₋₁₀alkyl, C₁₋₁₀perhaloalkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, halo, nitro, cyano, thiol,substituted thiol, hydroxyl, substituted hydroxyl, amino,monosubstituted amino, and disubstituted amino;

G is —O— or —S—;

y is 0, 1, or 2;

x is 0 or 1; and

n is 0 or an integer of from 1 to 5, inclusive.

In certain embodiments of Formula (I-a), wherein R₃′ is hydrogen, thecompound is of Formula (I-b):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments of Formula (I-a), wherein R₃ is hydrogen, thecompound is of Formula (I-c):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments of Formula (I-a), wherein G is —O—, provided is acompound of Formula (I-a1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein; wherein

, R₁, R₂, R₃, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-b), wherein G is —O—, the compoundis of Formula (I-b1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-c), wherein G is —O—, the compoundis of Formula (I-c1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-a), wherein G is —S—, provided is acompound of Formula (I-a2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-b), wherein G is —S—, the compoundis of Formula (I-b2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-c), wherein G is —S—, the compoundis of Formula (I-c2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments, the compound of Formula (I-a) has the followingstereochemistry, also referred to herein as a compound of Formula (I-d):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, Z, Y, G, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d), wherein R₃′ is hydrogen, thecompound is of Formula (I-e):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d), wherein R₃ is hydrogen, thecompound is of Formula (I-f):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′ Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments of Formula (I-d), wherein G is —O—, the compoundis of Formula (I-d1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, Z, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-e), wherein G is —O—, the compoundis of Formula (I-e1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-f), wherein G is —O—, the compoundis of Formula (I-f1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-d), wherein G is —S—, the compoundis of Formula (I-d2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, R₃′, Z, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-e), wherein G is —S—, the compoundis of Formula (I-e2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments of Formula (I-f), wherein G is —S—, the compoundis of Formula (I-f2):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments, Z is ═O.

In certain embodiments, each

represents a single bond.

In certain embodiments, each instance of R₁ and R₂ is —OH.

In certain embodiments of Formula (I-d2), wherein Z is ═O and each

represents a single bond, provided is a compound of Formula (I-g):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein X, Y, y, x, and n are as defined herein.

In certain embodiments, the compound for use in the present invention is

also referred to herein as CAY10509, or a pharmaceutically acceptablesalt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopicallyenriched derivative, or prodrug thereof.

In certain embodiments, the compound for use in the present invention is

also referred to herein as CAY10509 free acid, or a pharmaceuticallyacceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer,isotopically enriched derivative, or prodrug thereof.

In certain embodiments at least one exocyclic

represents a cis-double bond.

For example, in certain embodiments of Formula (I-d1), wherein eachinstance of R₁ and R₂ is —OH, and Z is ═O, provided is a compound ofFormula (I-e):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₃, R₃′, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-h), wherein R₃′ is hydrogen,provided is a compound of Formula (I-i):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₃, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (I-i), wherein R₃ is —OH, the compoundfor use in the present invention is of Formula (I-j):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein Y, X, y, x, and n are as defined herein.

In certain embodiments, the compound of Formula (I-j), wherein

is a trans double bond, X is —NHCH₂CH₃, y is 1, x is 0, and n is 0, isthe compound:

also referred to herein as 17-phenyl trinor prostaglandin F2α ethylamide, or bimatoprost; or a pharmaceutically acceptable salt, hydrate,solvate, stereoisomer, polymorph, tautomer, isotopically enrichedderivative, or prodrug thereof.

In certain embodiments, the compound of Formula (I-j), wherein

is a trans double bond, X is —OCH(CH₃)₂, y is 1, x is 0, and n is 0, isthe compound:

also referred to herein as 17-phenyl trinor prostaglandin F2α aisopropyl ester, or bimatoprost isopropyl ester; or a pharmaceuticallyacceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer,isotopically enriched derivative, or prodrug thereof.

In certain embodiments, the compound of Formula (I-j), wherein

is a trans double bond, X is —OH, y is 1, x is 0, and n is 0, is thecompound:

also referred to herein as 17-phenyl trinor prostaglandin F2α, orbimatoprost free acid; or a pharmaceutically acceptable salt, hydrate,solvate, stereoisomer, polymorph, tautomer, isotopically enrichedderivative, or prodrug thereof.

In certain embodiments, the compound of Formula (I-j), wherein

is a trans double bond, X is —OCH(CH₃)₂, y is 0, x is 1, and n is 1, isthe compound:

also referred to herein as fluprostenol isopropyl ester, or travoprost;or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof.

In certain embodiments, the compound of Formula (I-j), wherein

is a trans double bond, X is —OH, y is 0, x is 1, and n is 1, is thecompound:

also referred to herein as travoprost free acid; or a pharmaceuticallyacceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer,isotopically enriched derivative, or prodrug thereof.

In certain embodiments, the compound of Formula (I-j), wherein

is a single bond, X is —OCH(CH₃)₂, y is 1, x is 0, and n is 0, is thecompound:

also referred to herein as 17-phenyl-13,14-dihydro trinor prostaglandinF2α isopropyl ester, or latanoprost; or a pharmaceutically acceptablesalt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopicallyenriched derivative, or prodrug thereof.

In certain embodiments, the compound of Formula (I-j), wherein

is a single bond, X is —OH, y is 1, x is 0, and n is 0, is the compound:

also referred to herein as latanoprost free acid; or a pharmaceuticallyacceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer,isotopically enriched derivative, or prodrug thereof.

In certain embodiments of Formula (I-h), wherein R₃ is F and R₃′ is F,the compound for use in the present invention is of Formula (I-k):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, Y, X, y, x, and n are as defined herein.

In certain embodiments, the compound of Formula (I-k), wherein

is a trans double bond, X is —OCH(CH₃)₂, y is 1, x is 1, and n is 0, isthe compound:

also referred to herein as tafluprost; or a pharmaceutically acceptablesalt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopicallyenriched derivative, or prodrug thereof.

In certain embodiments, the compound of Formula (I-k), wherein

is a trans double bond, X is —OH, y is 1, x is 1, and n is 0, is thecompound:

also referred to herein as tafluprost free acid; or a pharmaceuticallyacceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer,isotopically enriched derivative, or prodrug thereof.

In certain embodiments of Formula (I), the compound of Formula (I-l):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein;

each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration;

each instance of R₃ and R₃′ is independently hydrogen, halogen, —OH,substituted hydroxyl, or —O(CO)R₈, wherein R₈ is optionally substitutedC₁₋₂₀alkyl, optionally substituted C₂₋₂₀alkenyl, optionally substitutedC₂₋₂₀alkynyl, or —(CH₂)_(m)R₉ wherein m is 0 or an integer between 1-10,inclusive, and R₉ is optionally substituted C₃₋₇carbocyclyl, optionallysubstituted C₆₋₁₀aryl, or optionally substituted5-14-membered-heteroaryl, or R₃ and R₃′ are joined to form ═O;

Y is selected from the group consisting of optionally substitutedC₁₋₁₀alkyl, C₁₋₁₀perhaloalkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, halo, nitro, cyano, thiol,substituted thiol, hydroxyl, substituted hydroxyl, amino,monosubstituted amino, and disubstituted amino;

G is —O— or —S—;

y is 0, 1, or 2;

x is 0 or 1; and

n is 0 or an integer of from 1 to 5, inclusive.

In certain embodiments of Formula (I-l), wherein Z is ═O, and R₁ and R₂are each —OH, provided is a compound of Formula (I-m):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein.

In certain embodiments of Formula (I-m), wherein R₃′ is hydrogen, y is 2and x is 0, provided is a compound of Formula (I-n):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein.

In certain embodiments, the compound of Formula (I-n), wherein R₃ is—OH, and X is —OH, is the compound:

also referred to as AL-16082, or a pharmaceutically acceptable salt,hydrate, solvate, stereoisomer, polymorph, tautomer, isotopicallyenriched derivative, or prodrug thereof; wherein R₁, R₂, Z, and X are asdefined herein. See, e.g., Feng et al, supra, incorporated herein byreference.

In certain embodiments, the compound useful in the present invention isof Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof;

wherein each instance of

independently represents a single bond or a double bond which can be inthe cis or trans configuration;

A is alkylene or alkenylene having from two to six carbon atoms, whereinthe alkylene or alkenylene group is optionally interrupted by one ormore —O— groups and optionally substituted with one or more halogen,hydroxy, oxo, alkyloxy or alkylcarboxy groups, wherein each instance ofalkyl alone or part of another group independently comprises from one tosix carbon atoms;

B is cycloalkyl having from three to seven carbon atoms, aryl havingfrom six to ten carbon atoms, or heteroaryl having from four to tencarbon atoms and one to four heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur;

X is —OR₄ or —N(R₄)₂, wherein R₄ is selected from the group consistingof hydrogen, alkyl having from one to six carbon atoms, —C(═O)R₅, or—C(═O)OR₅, wherein R₅ is alkyl having from one to six carbon atoms;

Z is ═O or represents two hydrogen atoms; and

one of R₁ and R₂ is ═O, —OH, or a —O(CO)R₆ group and the other one is—OH or —O(CO)R₆, or R₁ is ═O and R₂ is H, wherein R₆ is a saturated orunsaturated acyclic hydrocarbon group having from 1 to about 20 carbonatoms or —(CH₂)_(m)R₇ wherein m is 0-10, and R₇ is cycloalkyl havingfrom three to seven carbon atoms, aryl having from six to ten carbonatoms, or heteroaryl having from four to ten carbon atoms and one tofour heteroatoms selected from the group consisting of nitrogen, oxygenand sulfur.

As generally defined above, in certain embodiments, the compound usefulin the present invention is of Formula (II):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof;wherein A, B, X, Z, L, and R₁ are as defined herein. are as definedherein.

In certain embodiments, L is a group of the formula

wherein

represents a single bond.

In certain embodiments, L is a group of the formula

wherein

represents a double bond which can be in the cis or trans configuration.In certain embodiments, the double bond is in the cis configuration. Incertain embodiments, the double bond is in the trans configuration

In certain embodiments, L is a group of the formula

wherein

represents a single bond.

In certain embodiments, L is a group of the formula

wherein

represents a double bond which can be in the cis or trans configuration.In certain embodiments, the double bond is in the cis configuration. Incertain embodiments, the double bond is in the trans configuration

In certain embodiments of Formula (II), the compound of Formula (II-a):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, Z, and X are as defined herein; wherein

, R₁, Z, X, Y, G, R₃, R₃′, y, x, and n are as defined herein.

In certain embodiments of Formula (II-a), wherein R₃′ is hydrogen, thecompound is of Formula (II-b):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₃, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments of Formula (II-a), wherein R₃ is hydrogen, thecompound is of Formula (II-c):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₂, R₃′, Z, X, Y, G, y, x, and n are as defined herein.

In certain embodiments, G is —O—. In certain embodiments, G is —S—.

In certain embodiments of Formula (II-a), wherein G is —O—, provided isa compound of Formula (II-a1):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein R₁, R₂, Z, and X are as defined herein; wherein

, R₁, R₂, R₃, R₃′, Z, X, Y, y, x, and n are as defined herein.

In certain embodiments, Z is ═O.

In certain embodiments at least one exocyclic

represents a cis-double bond.

For example, in certain embodiments of Formula (II-a1), wherein Z is ═O,provided is a compound of Formula (II-d):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, R₁, R₃, R₃′, Y, X, y, x, and n are as defined herein.

In certain embodiments of Formula (II-d), wherein R₁ is OH, R₃′ ishydrogen, R₃ is —OH, y is 0, and x is 1, provided is a compound ofFormula (II-e):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,polymorph, tautomer, isotopically enriched derivative, or prodrugthereof; wherein

, Y, X, and n are as defined herein.

In certain embodiments of Formula (II-e), wherein X is —OCH(CH₃)₂, thecompound is:

also referred to as AL-12182, or a pharmaceutically acceptable salt,hydrate, solvate, stereoisomer, polymorph, tautomer, isotopicallyenriched derivative, or prodrug thereof; wherein

, Y, X, and n are as defined herein.

In certain embodiments of Formula (II-e), wherein X is —OH, the compoundis:

also referred to as AL-12182 free acid, or a pharmaceutically acceptablesalt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopicallyenriched derivative, or prodrug thereof; wherein

, Y, X, and n are as defined herein.

Other compounds of Formula (II) for use in the present invention arecontemplated herein; See, e.g., Selliah et al, supra, incorporatedherein by reference.

In certain embodiments, the compound of Formula (I) or (II) is a prodrugof any one of the compounds described herein. Exemplary prodrugs includeesters, amides, and/or thioamides of the parent free acid and acylgroups present on the pentacyclic hydroxyl groups. Without being boundby any particular theory, the invention envisions that the free acid ofcompounds described herein (e.g. for example, wherein Z is ═O, and X is—OH, such as, but not limited to bimatoprost free acid, travoprost freeacid, latanoprost free acid, tafluprost free acid, or salts thereof)represents the principal pharmacologically active compound (“activemetabolite”) for the purposes of this invention. It is also envisionedthat certain compounds of the present invention will serve as substratesfor hydrolases in the body (e.g., esterases such as lipases, amidases),which will in turn produce the corresponding free acid in vitro or invivo.

Pharmaceutical Compositions and Formulations

In certain embodiments, the present invention provides pharmaceuticalcompositions and formulations for use in any of the inventive methods,described herein, comprising one or more compounds of the Formula (I) or(II) described herein (the “active ingredient”) and a pharmaceuticallyacceptable excipient.

Pharmaceutically acceptable excipients include any and all solvents,diluents or other liquid vehicles, dispersion or suspension aids,surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. General considerations in theformulation and/or manufacture of pharmaceutical compositions agents canbe found, for example, in Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), andRemington: The Science and Practice of Pharmacy, 21^(st) Edition(Lippincott Williams & Wilkins, 2005).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the active ingredient intoassociation with a carrier and/or one or more other accessoryingredients, and then, if necessary and/or desirable, shaping and/orpackaging the product into a desired single- or multi-dose unit.

In certain embodiment, the pharmaceutical composition is formulated as atime relase formulation, e.g., a sustained-release (SR),sustained-action (SA), extended-release (ER, XR, or XL), timed-release(TR), controlled-release (CR), modified release (MR), andcontinuous-release (CR) formulations, refer to dosage forms useful inreleasing an active ingredient at a predetermined rate by maintaining aconstant level of the active ingredient or active metabolite thereof inthe bloodstream for a specific period of time with minimum side effect.Time release formulations may comprise imbedding the active ingredientin a matrix of insoluble particles, micro-encapsulation, use ofliposomes and/or use of gels (e.g., hydrogels).

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable carrier, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, etc., and combinationsthereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, etc., and combinations thereof.

Exemplary surface active agents and/or emulsifiers includelipids/natural emulsifiers (e.g. acacia, agar, alginic acid, sodiumalginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin,egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidalclays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminumsilicate]), long chain amino acid derivatives, high molecular weightalcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylenesorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60],polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate[Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span65], glyceryl monooleate, sorbitan monooleate [Span 80]),polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45],polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and Solutol), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethyleneethers, (e.g. polyoxyethylene lauryl ether [Brij 30]),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, etc. and/or combinations thereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, etc., and/or combinations thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, etc., and combinations thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, etc., and combinations thereof.

Exemplary oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary oils include, but are not limited to, butylstearate, caprylic triglyceride, capric triglyceride, cyclomethicone,diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil,octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

A pharmaceutical formulation may comprise excipients that cause theactive pharmaceutical ingredient(s) to be transported, trafficked,deposited, concentrated, and/or retained in adipose tissue or morespecifically, in or near an adipocyte. For example, a “lipophilicexcipient” (e.g., selected from the group consisting of an liposomes,oil, a surface active agent, an emulsifier, or a mixture thereof, asdefined above and herein) may be used in an enteral (e.g., oral)formulation, whereby the active ingredient is administered with alipophilic excipient, which together are absorbed by enterocytes of thesmall intestine and formed into chylomicrons, which are in turnpreferentially transported by the bloodstream to adipose tissue. As analternative example, liposomes may be used as a lipophilic excipient forenteral, parenteral, or topical formulation.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredient,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents (e.g., ethylcarbonate, ethyl acetate, benzyl benzoate, dimethylformamide), fattyacid esters of sorbitan, polysorbates, solubilizing agents such asalcohols (e.g., ethyl alcohol, isopropyl alcohol, tetrahydrofurfurylalcohol, benzyl alcohol, glycerol and glycols (e.g., 1,3-butyleneglycol, propylene glycol, polyethylene glycols)), oils (e.g.,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),Cremophor, cyclodextrins, polymers) and mixtures thereof. Besides inertdiluents, the oral compositions can include adjuvants such as wettingagents, emulsifying and suspending agents, sweetening, flavoring, andperfuming agents. In certain embodiments, for parenteral administration,the active ingredient is mixed with solubilizing agents such asCremophor, alcohols, oils, modified oils, glycols, polysorbates,cyclodextrins, polymers, and combinations thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may comprise buffering agents.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes. Solid compositions of asimilar type can be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active ingredient can be provided in micro-encapsulated form withone or more excipients as noted above. The solid dosage forms oftablets, dragees, capsules, pills, and granules can be prepared withcoatings and shells such as enteric coatings, release controllingcoatings and other coatings well known in the pharmaceutical formulatingart. In such solid dosage forms the active ingredient can be admixedwith at least one inert diluent such as sucrose, lactose or starch. Suchdosage forms may comprise, as is normal practice, additional substancesother than inert diluents, e.g., tableting lubricants and othertableting aids such a magnesium stearate and microcrystalline cellulose.In the case of capsules, tablets and pills, the dosage forms maycomprise buffering agents. They may optionally comprise opacifyingagents and can be of a composition that they release the activeingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embeddingcompositions which can be used include polymeric substances and waxes.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the active ingredient witha suitable non-irritating excipient or carrier such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active ingredient.

In certain embodiments, the pharmaceutical composition further comprisesone or more excipients adapted for transdermal administration. Dosageforms for topical and/or transdermal administration of an activeingredient may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier and/or any needed preservativesand/or buffers as can be required. Additionally, the present inventioncontemplates the use of transdermal patches, which often have the addedadvantage of providing controlled delivery of an active ingredient tothe body. Such dosage forms can be prepared, for example, by dissolvingand/or dispensing the active ingredient in the proper medium.Alternatively or additionally, the rate can be controlled by eitherproviding a rate controlling membrane and/or by dispersing the activeingredient in a polymer matrix and/or gel. Exemplary carriers fortransdermal administration include dimethyl sulfoxide, HRT (hormonereplacement therapy) base, Pluronic™ lecithin organogel, Lipoderm®,Vanpen®, Aladerm®, and anhydrous gels.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices that limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices that deliver liquid vaccines to the dermis via aliquid jet injector and/or via a needle that pierces the stratum corneumand produces a jet that reaches the dermis are suitable. Jet injectiondevices are described, for example, in U.S. Pat. Nos. 5,480,381;5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911;5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627;5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; andPCT publications WO 97/37705 and WO 97/13537. Ballistic powder/particledelivery devices that use compressed gas to accelerate vaccine in powderform through the outer layers of the skin to the dermis are suitable.Alternatively or additionally, conventional syringes can be used in theclassical mantoux method of intradermal administration.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi liquid preparations such as liniments,lotions, oil in water and/or water in oil emulsions such as creams,ointments and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations may, for example, comprise fromabout 0.3% to about 10% (w/w) or (w/v) of the active ingredient,although the concentration of the active ingredient can be as high asthe solubility limit of the active ingredient in the solvent.Formulations for topical administration may further comprise one or moreof the additional ingredients described herein.

A pharmaceutical composition can be prepared, packaged, and/or sold in aformulation suitable for pulmonary administration via the buccal cavity.Such a formulation may comprise dry particles which comprise the activeingredient and which have a diameter in the range from about 0.5 toabout 7 nanometers or from about 1 to about 6 nanometers. Suchcompositions are conveniently in the form of dry powders foradministration using a device comprising a dry powder reservoir to whicha stream of propellant can be directed to disperse the powder and/orusing a self propelling solvent/powder dispensing container such as adevice comprising the active ingredient dissolved and/or suspended in alow-boiling propellant in a sealed container. Such powders compriseparticles wherein at least 98% of the particles by weight have adiameter greater than 0.5 nanometers and at least 95% of the particlesby number have a diameter less than 7 nanometers. Alternatively, atleast 95% of the particles by weight have a diameter greater than 1nanometer and at least 90% of the particles by number have a diameterless than 6 nanometers. Dry powder compositions may include a solid finepowder diluent such as sugar and are conveniently provided in a unitdose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions formulated for pulmonary delivery mayprovide the active ingredient in the form of droplets of a solutionand/or suspension. Such formulations can be prepared, packaged, and/orsold as aqueous and/or dilute alcoholic solutions and/or suspensions,optionally sterile, comprising the active ingredient, and mayconveniently be administered using any nebulization and/or atomizationdevice. Such formulations may further comprise one or more additionalingredients including, but not limited to, a flavoring agent such assaccharin sodium, a volatile oil, a buffering agent, a surface activeagent, and/or a preservative such as methylhydroxybenzoate. The dropletsprovided by this route of administration may have an average diameter inthe range from about 0.1 to about 200 nanometers.

The formulations described herein as being useful for pulmonary deliveryare useful for intranasal delivery of a pharmaceutical composition ofthe invention. Another formulation suitable for intranasaladministration is a coarse powder comprising the active ingredient andhaving an average particle from about 0.2 to 500 micrometers. Such aformulation is administered, by rapid inhalation through the nasalpassage from a container of the powder held close to the s suitable fornasal administration may, for example, comprise from about as little as0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and maycomprise one or more of the additional ingredients described herein. Apharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for buccal administration. Suchformulations may, for example, be in the form of tablets and/or lozengesmade using conventional methods, and may contain, for example, 0.1 to20% (w/w) active ingredient, the balance comprising an orallydissolvable and/or degradable composition and, optionally, one or moreof the additional ingredients described herein. Alternately,formulations suitable for buccal administration may comprise a powderand/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.1 to about 200 nanometers,and may further comprise one or more of the additional ingredientsdescribed herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for ophthalmic administration.Such formulations may, for example, be in the form of eye dropsincluding, for example, a 0.1/1.0% (w/w) solution and/or suspension ofthe active ingredient in an aqueous or oily liquid carrier. Such dropsmay further comprise buffering agents, salts, and/or one or more otherof the additional ingredients described herein. Otherophthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are contemplated asbeing within the scope of this invention.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions that aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.General considerations in the formulation and/or manufacture ofpharmaceutical compositions can be found, for example, in Remington: TheScience and Practice of Pharmacy 21st ed., Lippincott Williams &Wilkins, 2005.

Still further encompassed by the invention are kits comprising acompound as described herein and instructions for use. Kits provided maycomprise a provided composition and a container (e.g., a vial, ampoule,bottle, syringe, and/or dispenser package, or other suitable container).In some embodiments, provided kits may optionally further include asecond container comprising a suitable aqueous carrier for dilution orsuspension of the provided composition for preparation of administrationto a subject. In some embodiments, contents of provided formulationcontainer and solvent container combine to form at least one unit dosageform.

The active ingredient can be administered using any amount and any routeof administration effective for treatment. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular composition, its mode of administration, its mode ofactivity, and the like.

The active ingredient is typically formulated in dosage unit form forease of administration and uniformity of dosage. It will be understood,however, that the total daily usage of the compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject will depend upon a variety of factorsincluding the condition being treated and the severity of the condition;the activity of the specific active ingredient employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the subject; the time of administration, route of administration, andrate of excretion of the specific active ingredient employed; theduration of the treatment; drugs used in combination or coincidentalwith the specific active ingredient employed; and like factors wellknown in the medical arts.

The active ingredient can be administered by any route, includingenteral (e.g., oral, rectal), parenteral (e.g., intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, interdermal), and topical administration(e.g., transdermal, transmucosal).

In certain embodiments, the active ingredient is administeredsystemically. As used herein, “systemic administration” or“administering systemically” or “systemic effect” means administrationto the subject by enteral, parenteral, or topical (e.g., transdermal)administration, whereby the active ingredient or active metabolitethereof reaches and maintains a therapeutically effective concentrationin the bloodstream for a period of time. A systemic effect isdistinguishable from a local effect in a variety of ways, e.g., forexample, as demonstrated in Example 1, a systemic effect is indicativeof fat reduction in both treated and untreated areas of a subject'sbody.

In certain embodiments, “systemic administration” or “administeringsystemically” or “systemic effect” refers to the administration of anactive ingredient to the subject, whereby the active ingredient oractive metabolite thereof reaches and maintains a therapeuticallyeffective concentration in the bloodstream for at least 4 hours, atleast 8 hours, at least 10 hours, at least 12 hours, at least 15 hours,at least 24 hours, between 4 hours and 24 hours, between 8 hours and 24hours, between 10 hours and 24 hours, or between 15 hours and 24 hours.In certain embodiments, the administration is transdermaladministration. Without wishing to be bound by any particular theory,even if the active ingredient is eliminated rapidly from the bloodstream(e.g., latanoprost has a serum elimination half-life of about 17minutes), transdermal administration can provide a depot effect wherebya single application to the skin can result in slow release of theactive ingredient into the bloodstream, and thereby result in a moresustained therapeutically effective concentration in the bloodstream.Other formulations or techniques, such as time release formulations orcontinuous IV infusion, may enable this desired slow release of theactive ingredient via other routes of administration.

In certain embodiments, the active ingredient is administered to thesubject twice daily, daily, every 3 days, or weekly for at least 1 week,at least 2 weeks, at least one month, at least 2 months, at least 3months, at least 4 months, at least 5 months, at least 6 months, between1 week to 6 months, between 2 weeks to 6 months, between 1 month to 6months, between 2 months to 6 months, between 3 months to 6 months,between 4 months to 6 months or between 5 months to 6 months. In certainembodiments, the administration is transdermal administration. Incertain embodiments, the active ingredient is administered transdermallyonce daily.

The exact amount of the active ingredient required to achieve atherapeutically effective amount will vary from subject to subject,depending, for example, on species, age, and general condition of asubject, severity of the side effects or disorder, identity of theparticular compound(s), mode of administration, and the like. Thedesired dosage can be delivered three times a day, two times a day, oncea day, every other day, every third day, every week, every two weeks,every three weeks, or every four weeks. In certain embodiments, thedesired dosage can be delivered using multiple administrations (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or more administrations). As demonstrated in theaccompanying Examples, daily administration to the subject can beadequate (but not necessarily preferable) to achieve the desired effect.A daily administration schedule is considered convenient for human use.The active ingredient may be administered by the subject to himself orherself repeatedly and without special equipment or training, although amedical professional also can also administer the active ingredient tothe subject.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

In certain embodiments, a therapeutically effective concentration of thecompound is in the range of about 50 pg/ml and 1000 pg/ml, inclusive,e.g., greater than 50 pg/ml, greater than 60 pg/ml, greater than 70pg/ml, greater than 80 pg/ml, greater than 90 pg/ml, greater than 100pg/ml, greater than 150 pg/ml, greater than 200 pg/ml, greater than 250pg/ml, greater than 300 pg/ml, greater than 350 pg/ml, greater than 400pg/ml, greater than 450 pg/ml, greater than 500 pg/ml, greater than 550pg/ml, greater than 600 pg/ml, greater than 650 pg/ml, greater than 700pg/ml, greater than 750 pg/ml, greater than 800 pg/ml, greater than 850pg/ml, greater than 900 pg/ml, greater than 950 pg/ml. The presentinvention contemplates a significant amount of compound or activemetabolite thereof, e.g., the free acid, to appear systemically, i.e.,in the blood. However, the concentration is not necessarily maintainedwithin this range throughout the entire dosing interval, and mayfluctuate during the dosing interval.

In certain embodiments, the compound is administered, e.g., orally,subcutaneously, or intravenously, at a dose of between about 0.5 mg in a24-hour period and about 50 mg in a 24-hour period, inclusive, e.g.,between about 0.5 mg to about 40 mg, between about 0.5 mg to about 30mg, between about 0.5 mg to about 20 mg, between about 0.5 mg to about10 mg, between about 0.5 mg to about 5 mg, between about 1 mg to about50 mg, between about 10 mg to about 50 mg, between about 15 mg to about50 mg, between about 20 mg to about 50 mg, between about 30 mg to about50 mg, between about 40 mg to about 50 mg, in a 24-hour period,inclusive.

In certain embodiments, the compound is administered, e.g., to the skin,at a dose of between about 3 mg in a 24-hour period and about 50 mg in a24-hour period, inclusive, e.g., between about 3 mg to about 40 mg,between about 3 mg to about 30 mg, between about 3 mg to about 20 mg,between about 3 mg to about 10 mg, between about 3 mg to about 5 mg,between about 5 mg to about 50 mg, between about 10 mg to about 50 mg,between about 20 mg to about 50 mg, between about 30 mg to about 50 mg,or between about 40 mg to about 50 mg, in a 24-hour period, inclusive.

In certain embodiments, the compound is administered, e.g., to the skin,and delivered to bloodstream of a subject a dose between about 0.05 mgand about 2 mg per hour, inclusive, e.g., between about 0.1 mg and about2 mg, between about 0.5 mg and about 2 mg, between about 1 mg and about2 mg, per hour, inclusive.

In certain embodiments, the compound is administered to the skin by atransdermal patch or gel.

In certain embodiments, a composition comprises greater than or equal toabout 0.3% (w/v) of the active ingredient in order to achieve a systemiceffect. In certain embodiments, the composition comprises greater than0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%,6.0%, 7.0%, 8.0%, 9.0%, or 10.0% (w/v) of the active ingredient. Incertain embodiments, the composition comprises between about 0.4% andabout 10%, weight per volume, inclusive. In certain embodiments, thecomposition comprises between about 0.4% and about 2%, weight pervolume, inclusive.

In a particular embodiment, a composition for application to the skincomprises at or greater than or equal to about 0.3% (w/v) of the activeingredient in order to achieve a systemic effect. In certainembodiments, the composition comprises greater than 0.3%, 0.4%, 0.5%,0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%,9.0%, or 10.0% (w/v) of the active ingredient. In certain embodiments,the composition comprises between about 0.4% and about 10%, weight pervolume, inclusive. In certain embodiments, the composition comprisesbetween about 0.4% and about 2%, weight per volume, inclusive.

In a particular embodiment, a composition for subcutaneous injectioncomprises at or greater than or equal to 0.05% (w/v) of the activeingredient in order to achieve a systemic effect. In certainembodiments, the composition comprises greater than 0.1%, 0.3%, 0.5%,1%, 2%, 3%, 4%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, or 10.0% (w/v) of theactive ingredient. In certain embodiments, the composition comprisesbetween about 0.4% and about 10%, weight per volume, inclusive. Incertain embodiments, the composition comprises between about 0.4% andabout 2%, weight per volume, inclusive.

In certain embodiments, the compound is administered at a dose of about0.5 mg/m²/d to about 50 mg/m²/d, e.g., between about 0.5 mg/m²/d toabout 40 mg/m²/d, between about 0.5 mg/m²/d to about 30 mg/m²/d, betweenabout 0.5 mg/m²/d to about 20 mg/m²/d, between about 0.5 mg/m²/d toabout 10 mg/m²/d, between about 0.5 mg/m²/d to about 5 mg/m²/d, betweenabout 0.5 mg/m²/d to about 4 mg/m²/d, between about 1 mg/m²/d to about 5mg/m²/d, between about 2 mg/m²/d to about 5 mg/m²/d, between about 3mg/m²/d to about 5 mg/m²/d, between about 3 mg/m²/d to about 4 mg/m²/d,between about 5 mg/m²/d to about 50 mg/m²/d, between about 10 mg/m²/d toabout 50 mg/m²/d, between about 20 mg/m²/d to about 50 mg/m²/d, betweenabout 30 mg/m²/d to about 50 mg/m²/d, or between about 40 mg/m²/d toabout 50 mg/m²/d, in a 24-hour period, inclusive.

It is appreciated that more potent compounds may be administered atlower dosages than less potent compounds. For example, as shown inExample 3, a latanoprost dose of about 3.7 mg/m²/d may be acceptable forsystemic therapy, but for more potent compounds the systemic dose couldbe lower.

It will be also appreciated that the active ingredient can beadministered in combination with one or more additional therapeuticallyactive agents (“agents” or “active agents”). The compound or compositioncan be administered concurrently with, prior to, or subsequent to, oneor more additional agents. In general, the active ingredient and eachadditional active agent will be administered at a dose and/or on a timeschedule determined for the ingredient and agent. In will further beappreciated that the active ingredient and active agent utilized in thiscombination can be administered together in a single composition oradministered separately in different compositions. The particularcombination to employ in a regimen will take into account compatibilityof the active ingredient with the active agent and/or the desiredtherapeutic effect to be achieved. In general, it is expected thatadditional active agents utilized in combination be utilized at levelsthat do not exceed the levels at which they are utilized individually.In some embodiments, the levels utilized in combination will be lowerthan those utilized individually.

The active ingredient can be administered in combination with activeagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body. It will also be appreciated that therapy employed mayachieve a desired effect for the same disorder (for example, an activeingredient can be administered in combination with an anti-inflammatoryand/or anti-depressive agent, etc.), and/or it may achieve differenteffects (e.g., control of adverse side-effects).

Exemplary active agents include, but are not limited to, anti-obesityagents, steroidal agents, steroidal anti-inflammatory agent,non-steroidal anti-inflammatory agents, hormones, prostaglandins,progestational agents, anti-glaucoma agents, ophthalmic agents,diuretics, cardiovascular active agents, vasoactive agents, vasodilatingagents, anti-hypertensive agents, angiogenic agents, or modulators ofcell-extracellular matrix interactions (e.g. cell growth inhibitors andanti-adhesion molecules). Active agents include small organic moleculessuch as drug compounds (e.g., compounds approved by the Food and DrugsAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins and cells.

Methods for Treating a Disorder associated with metabolic syndrome

In one aspect, the invention provides a method of treating and/orpreventing a metabolic syndrome or a disorder associated with metabolicsyndrome in a subject in need thereof, comprising administering to asubject a compound of Formula (I) or (II).

The method encompasses administering one or more compounds of Formula(I) or (II) to a subject by any contemplated systemic route in an amountsufficient to treat and/or prevent metabolic syndrome or a disorderassociated with metabolic syndrome in the subject. In certainembodiments, the compound is systemically administered to a subjecttransdermally. In certain embodiments, the compound is systemicallyadministered to a subject orally. In certain embodiments, the compoundis systemically administered to a subject parenterally.

In some embodiments, the disorder associated with metabolic syndrome isselected from the group consisting of obesity, dyslipidemia, and adiabetic condition, as described herein.

Methods for Treating Obesity

In this aspect, the present invention provides a method of treatingand/or preventing obesity in a subject, comprising administering to asubject in need thereof one or more compounds of Formula (I) or (II).

The method encompasses administering one or more compounds of Formula(I) or (II) to a subject by any contemplated systemic route in an amountsufficient to treat and/or prevent obesity in the subject. In certainembodiments, the compound is systemically administered to a subjecttransdermally. In certain embodiments, the compound is systemicallyadministered to a subject orally. In certain embodiments, the compoundis systemically administered to a subject parenterally.

In certain embodiments, the present invention provides a method ofreducing adipocytes in a subject, comprising administering systemicallyto a subject in need thereof one or more compounds as described herein.Reducing adipocytes in a subject includes, but is not limited to,reducing fat cell amount (e.g., for example, fat cell number), reducingfat cell volume, reducing fat cell formation, reducing fat cellmaturation, dedifferentiating a fat cell, and/or inducing the death of afat cell (e.g., for example, by apoptosis) as measured by at least oneof volume, size, mass, bulk, density, amount, and/or quantity. Incertain embodiments, the method of reducing adipocytes comprisesreducing the fat cell amount, reducing fat cell volume, reducing fatcell formation, or reducing fat cell maturation, in a subject by greaterthan or equal to 75%, greater than or equal to 70%, greater than orequal to 60%, greater than or equal to 50%, greater than or equal to40%, greater than or equal to 30%, greater than or equal to 25%, greaterthan or equal to 20%, greater than or equal to 15%, greater than orequal to 10%, or greater than or equal to 5%. Treating obesity caninclude reducing body weight or reducing body mass index (BMI). Thepresent invention is expected to reduce body weight by greater than orequal to 75%, greater than or equal to 70%, greater than or equal to60%, greater than or equal to 50%, greater than or equal to 40%, greaterthan or equal to 30%, greater than or equal to 25%, greater than orequal to 20%, greater than or equal to 15%, greater than or equal to10%, or greater than or equal to 5%.

Treating obesity can include reducing body fat, as measured by at leastone of volume, size, mass, bulk, density, amount, and/or quantity. Bodyfat can be measured by skin calipers, dual energy x-ray Absorptiometry(DEXA), computed tomography (CT), magnetic resonance imaging (MRI), orany other suitable method known in the art, The measurement can be oftotal body fat, or only body fat on a particular part of the body. Fatreduction can also include reducing fat cell amount (for example, fatcell number), reducing fat cell volume, reducing fat cell maturation,and/or dedifferentiating a fat cell. These phenomena can be seen andmeasured, for example, by histologic examination of body fat.

The present invention is expected to reduce fat by greater than or equalto 75%, greater than or equal to 70%, greater than or equal to 60%,greater than or equal to 50%, greater than or equal to 40%, greater thanor equal to 30%, greater than or equal to 25%, greater than or equal to20%, greater than or equal to 15%, greater than or equal to 10%, orgreater than or equal to 5%.

In certain embodiments, the subject is overweight. “Overweight” is amedical condition, and is defined by the subject's BMI. Any subject witha BMI of greater than or equal to 25 is considered overweight. Anoverweight subject encompasses pre-obese subjects (e.g., having a BMI ofbetween 25 and 30) and obese subjects (e.g., having a BMI of greaterthan or equal to 30). In some embodiments of the invention, methods orcompositions used to treat or prevent “obesity” can likewise be used totreat or prevent “overweight” or “pre-obesity.”

In certain embodiments, the overweight subject is obese and suffers fromobesity. Any subject with a BMI of between 35 and 40, inclusive, isconsidered “severely obese” and suffers from “severe obesity”. Anysubject with a BMI between 40 and 45 is considered “morbidly obese” andsuffers from “morbid obesity”. Any subject with a BMI greater than orequal to 45 is considered “super obese” and suffers from “superobesity”.

In certain embodiments, the subject has obesity as a side effect ofmedication (e.g., for example, cortisol and analogs, corticosteroids,megace, sulfonylureas, anti-retrovirals, antidepressants, monoamineoxidase inhibitors, selective serotonin reuptake inhibitors, oralcontraceptives, insulin or a form of insulin, risperidone, clozapine,and thiazolidinediones).

In certain embodiments, the subject has obesity due to changes inhormonal status (e.g., as a result of physiologic changes such aspregnancy or menopause).

In certain embodiments, the subject with obesity is undergoing or hasrecently undergone smoking cessation.

In certain embodiments, the subject with obesity is also suffering orlikely to suffer from diabetes, hypertension, hyperlipidemia, coronaryartery disease, stroke, sleep apnea, gallbladder disease,gastroesophogeal reflux disease, fatty liver disease, gout,thromboembolism, elevated blood pressure, elevated blood sugar, elevatedserum cholesterol, elevated serum uric acid, cancer (e.g., breastcancer, colon cancer, lipomas, fatty tumors, particularly if there aremultiple fatty tumors), or a genetic disorder or medical conditioncharacterized at least in part by excess body fat (e.g., Cushingsyndrome, pseudo-Cushing syndrome, drug-induced obesity, HIV-relatedlipodystrophy, partical lipodystrophy, benign symmetric lipomatosis,Madelung's disease, hypothyroidism, pseudohypoparathyroidism,hypothalamic obesity, polycystic ovarian disease, depression, bingeeating, Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome,Down syndrome, Turner syndrome, growth hormone deficiency, growthhormone resistance, and leptin deficiency or resistance). The presentinvention contemplates treating any such disease, disorder, or conditionusing any of the described inventive methods.

In certain embodiments, the subject is not overweight. For example, themethod of reducing body fat in a subject is contemplated useful for notonly treating obesity in a subject, but also useful in treating subjectswho are not overweight, but still desire to increase the proportion oflean body mass to total body mass.

In certain embodiments, the subject does not suffer from metabolicsyndrome.

In certain embodiments, the methods of the present invention are usefulfor treating or preventing an adipocyte-related disease. As used herein,“adipocyte-related disease” means a disease: (i) wherein reduction ofadipocytes treats the disease, disorder, or condition from which thesubject is suffering; or (ii) whose mechanism comprises an adipocyteand/or its molecular products, e.g., secreted proteins, e.g.,adiponectin, resistin, tumor necrosis factor alpha (TNF-α),interleukin-6 (IL-6), C-reactive protein (CRP), fibrinogen, plasminogenactivator inhibitor-1 (PAI-1), and/or C-terminal binding protein (CtBP).Exemplary adipocyte-related diseases include, but are not limited to,metabolic syndrome, excess body fat (e.g., being overweight, obesity),dyslipidemia, hypercholesterolemia, hypertriglyceridemia, diabetes(e.g., type 2 diabetes), atherosclerosis, vascular disease, coronaryartery disease, stroke, cerebrovascular disease, peripheral vasculardisease, fatty liver, pancreatitis, inflammation or inflammatorydisease, depression, and dementia. In certain embodiments, theadipocyte-related disease is selected from the group consisting ofmetabolic syndrome, diabetes (e.g., type 2 diabetes), liver disease,atherosclerosis, fatty liver disease, inflammation or inflammatorydisease, depression, and dementia. In certain embodiments, treatment ofan adipocyte-related disease can be accomplished by reduction ofadipocytes that is microscopic rather than macroscopic, or diffuserather than focal.

Methods for Treating Dyslipidemia

In another aspect, provided is a method for treating and/or preventingdyslipidemia a subject in need thereof, comprising administering one ormore compounds of Formula (I) or (II) to the subject.

The method encompasses administering one or more compounds Formula (I)or (II) to a subject by any contempated route in an amount sufficient totreat and/or prevent dyslipidemia in the subject. In certainembodiments, the compound is systemically administered to a subjecttransdermally. In certain embodiments, the compound is systemicallyadministered to a subject orally. In certain embodiments, the compoundis systemically administered to a subject parenterally.

In certain embodiments, wherein the concentration of a lipid orlipoprotein in the blood is abnormally elevated, e.g., elevated serumtriglycerides or elevated LDL, the method reduces the concentration bygreater than or equal to 50%, by greater than or equal to 40%, bygreater than or equal to 30%, by greater than or equal to 25%, bygreater than or equal to 20%, by greater than or equal to 15%, bygreater than or equal to 10%, and/or by greater than or equal to 5%.

In certain embodiments, wherein the concentration of a lipid orlipoprotein in the blood is abnormally low, e.g., low HDL, the methodincreases the concentration by greater than or equal to 50%, by greaterthan or equal to 40%, by greater than or equal to 30%, by greater thanor equal to 25%, by greater than or equal to 20%, by greater than orequal to 15%, by greater than or equal to 10%, and/or by greater than orequal to 5%.

In certain embodiments, treating dyslipidemia comprises one or more of:reducing serum triglycerides, reducing serum total cholesterol, reducingserum LDL, and/or increasing serum HDL. In certain embodiments, thesubject suffers from or is likely to suffer from a disease, disorder, orcondition associated with dyslipidemia. In certain embodiments, thesubject suffers from or is likely to suffer from a disease, disorder orcondition selected from the group consisting of dyslipidemia,hypercholesterolemia, hypertriglyceridemia, a heritable disordercharacterized at least in part by one or more abnormal serum lipidlevels (e.g., familial hypercholesterolemia, familialhypertriglyceridemia), excess body fat (e.g., overweight, obesity),metabolic syndrome, vascular disease, atherosclerosis, coronary arterydisease, stroke, cerebrovascular disease, peripheral vascular disease,diabetes (e.g., type 2 diabetes), fatty liver disease, hepatic fibrosis,pancreatitis, inflammation or inflammatory disease, depression, anddementia.

In certain embodiments, the subject does not suffer from metabolicsyndrome.

Methods for Treating a Diabetic Condition

In another aspect, provided is a method for treating and/or preventing adiabetic condition in a subject in need thereof, comprisingadministering one or more compounds of Formula (I) or (II) to thesubject.

The method encompasses administering one or more compounds of Formula(I) or (II) to a subject by any contemplated systemic route in an amountsufficient to treat and/or prevent a diabetic condition in the subject.In certain embodiments, the compound is systemically administered to asubject transdermally. In certain embodiments, the compound issystemically administered to a subject orally. In certain embodiments,the compound is systemically administered to a subject parenterally.

In certain embodiments, treating a diabetic condition comprises one ormore of: reducing serum glucose, reducing glycated hemoglobin levels,reducing serum insulin, increasing insulin sensitivity, improvingglucose tolerance (e.g., reducing the glucose levels measured during aglucose tolerance test), reducing a subject's need for anothermedication (e.g., insulin) to maintain normal blood sugar levels, and/ortreating or preventing a diabetic complication.

In certain embodiments, the method reduces a serum glucoseconcentration, a glycated hemoglobin concentration, a serum insulinconcentration, a medication requirement (e.g., insulin requirement),and/or incidence or severity of a diabetic complication by greater thanor equal to 50%, by greater than or equal to 40%, by greater than orequal to 30%, by greater than or equal to 25%, by greater than or equalto 20%, by greater than or equal to 15%, by greater than or equal to10%, and/or by greater than or equal to 5%.

In certain embodiments, the subject suffers from or is likely to sufferfrom a disease, disorder or condition selected from the group consistingof type 2 diabetes mellitus, type 1 diabetes mellitus, prediabetes,hyperglycemia, insulin resistance, hyperinsulinemia, diabeticnephropathy, diabetic retinopathy, diabetic neuropathy, atherosclerosis,coronary artery disease, stroke, myocardial ischemia, myocardialinfarction, diabetic myocardial small vessel disease, diabeticgastroparesis, diabetic hearing loss, a diabetic skin disease, adiabetes-related infection, diabetic oral disease (e.g., gingivitis),diabetic acidosis (e.g., diabetic ketoacidosis), nonketotichypersosmolar state, coma, and diabetic foot ulcer.

In certain embodiments, the subject does not suffer from metabolicsyndrome.

Other Uses of the Compositions and Compounds

Given the ability of the compounds disclosed herein to reduce fat,adipocytes, and lipid concentrations, and the association of thesespecies with metabolic pathways and disease (e.g., as part of themetabolic syndrome), it is further envisioned that the compounds,compositions, and methods described herein may be used to lower one ormore of the following clinical parameters in a body: serum glucoseconcentration, glycated hemoglobin concentration (i.e., hemoglobin A1C,“HbA1c”), circulating insulin concentration, serum urate concentration,concentration(s) of hepatic serum biomarkers, e.g. transaminases, andconcentrations of pancreas-related serum biomarkers, e.g. amylase andlipase. As used herein, the term “serum glucose concentration” isintended to encompass any suitable measure of the concentration ofglucose in the blood.

It is further envisioned that compounds, compositions, and methodsdescribed herein may be used to improve an individual's response toinsulin (i.e., treat insulin resistance) or to leptin (i.e., treatleptin deficiency).

EXAMPLES

Throughout the description, where laboratory assays, e.g. for glucose orlipid concentrations, refer to a particular matrix, e.g. serum, it is tobe understood that such assays may, depending on the analyte, beconducted on other matrices or sample types, e.g. plasma, or with othertechnologies, e.g., noninvasive methods, that yield comparablemeasurements.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present invention may alsoconsist essentially of, or consist of, the recited components, and thatthe processes of the present invention may also consist essentially of,or consist of, the recited processing steps. Further, it should beunderstood that the order of steps or order for performing certainactions are immaterial so long as the invention remains operable.Moreover, two or more steps or actions may be conducted simultaneously.

In light of the foregoing description, the specific non-limitingexamples presented below are for illustrative purposes and not intendedto limit the scope of the invention in any way.

Example 1

A randomized, controlled, repeat-dose, 4-week trial was conducted on(db−/db−) mice, which are defective for the leptin receptor (JacksonLaboratories). These mice are genetically obese, dyslipidemic, anddiabetic.

Methods: Mice were obtained from Jackson Laboratories and acclimated tothe facility. At about 5 weeks of age, mice were prospectivelyrandomized into groups and assigned to the treatment conditions shown inFIG. 1. Topical treatments were applied in a thin film to the rightflank skin without occlusive dressings; subcutaneous injections werealso administered to the right flank. Mice were observed for conditionand weighed daily. They were housed in the same room, in 11 cagesaccording to group, and fed ad libitum. Skin tissue was sampled andserum lipids tested on day 28. Tissue was fixed in formalin and stainedwith hematoxylin and eosin.

Results: Animals fed and behaved normally throughout the study. Skincondition remained normal. Mean weight gain for days 0 to 28, by group,is shown in FIG. 2. Animals treated with vehicle only (Groups 1 and 2)showed an expected amount of weight gain for the strain (normative data,Jackson Laboratories). Transdermal bimatoprost isopropyl ester (BIE) andbimatoprost free acid (BFA) reduced weight gain significantly and in adose-dependent manner, but topical bimatoprost did not. SubcutaneousBIE, subcutaneous BFA, and intraperitoneal BFA had no significant effecton weight gain.

FIG. 3 shows representative histologic sections of skin and subcutaneousfat from untreated (left) and treated (right) flanks of animals assignedto vehicle only (Group 1), topical bimatoprost 0.3% (Group 4), andtopical BIE 0.3% (Group 11). All sections are shown at the samemagnification (scale bar at top right=640 microns). The surface of theskin is oriented toward the top and left of each panel. Arrows in eachsection denote the panniculus carnosus, an anatomic layer that separatesthe first layer of subdermal fat from deeper, subpannicular fat(separation artifact is commonly seen deep to the panniculus and is notan in vivo process).

In vehicle-only treated animals (Group 1), the adipose layer betweenskin and panniculus was thick, with approximately 10 pseudo-layers ofplump adipocytes.

In animals treated with topical bimatoprost 0.3%, smaller adipocytes anda thinner adipose layer were seen on the right (treated) flank but noton the left (untreated) flank. The untreated flank resembled that of avehicle-treated animal, with a thick adipose layer and plump adipocytes.This observation is consistent with a local effect, but not a systemiceffect, from topical bimatoprost at a concentration up to 0.3%.

In animals treated with topical BIE 0.3%, smaller adipocytes and thinneradipocyte layers were seen on both treated and untreated flanks. Theeffects were symmetric, indicative of a systemic effect. In contrast toanimals treated with vehicle or bimatoprost 0.3%, animals treated withBIE 0.3% also showed profound shrinkage of adipocytes deep to thepanniculus (toward bottom of each panel), closer to vasculature, andagain indicative of a systemic effect.

FIG. 4 shows mean, unfasted, serum lipid concentrations for each group(day 28), expressed as a percent reduction, relative to control (Group1). FIG. 5 charts the triglyceride and total cholesterol results (mg/dl)for the topical treatment conditions as follows: Group 1=C, 3=D, 4=E,5=F, 6=G, 10=H, 11=I.

Triglycerides were significantly reduced in animals treated withtransdermal BFA (0.1% or 0.3%), and even more so in those treated withtransdermal BIE (0.1% or 0.3%). Total cholesterol was significantlylower in animals treated with transdermal BIE 0.1%. Topical bimatoprosthad no significant effect on serum lipids. Subcutaneous BIE,subcutaneous BFA, and intraperitoneal BFA had no significant effect onserum lipids.

Thus, in a mouse model of obesity and dyslipidemia, the foregoingresults show reduced weight gain and serum lipids following transdermaladministration of BIE and BFA, but not bimatoprost. Histology pointed toa systemic effect of BIE at concentrations tested, which was not seenwith bimatoprost at the same concentrations. Thus, although adiposetissue was reduced by locally active treatment (e.g. by topicalbimatoprost 0.3%), significant reductions in serum lipids and overallbody weight appeared to occur only with systemically active treatment(e.g. topical BIE 0.3%).

For each of the above effects, transdermal BIE was more potent thattransdermal BFA. Neither subcutaneous nor intraperitoneal administrationof any compound had any significant effect due to the compound beingquickly metabolized and extruded from the system. Transdermaladministration appears to allow for a more slow exposure of the compoundover a more lengthy period of time, e.g., over the dosing interval.Time-release formulations for subcutaneous and intraperitonealadministration of these compounds are contemplated as conferring asystemic effect similar to transdermal administration.

Example 2

A controlled, repeat-dose, 4-week, dose-ranging study of latanoprosttransdermal cream was conducted in Zucker Diabetic Fatty (ZDF) rats(ZDF-Lepr^(fa)/Crl), which are defective for the leptin receptor, obese,hyperlipidemic, and diabetic.

Methods: Male ZDF rats, approximately 8 weeks old, were obtained fromJackson Laboratories and acclimated to the facility. They wereprospectively assigned to treatment conditions shown in FIG. 6. Therewere 3 animals per treatment arm. Test articles were applied in a thinfilm to the right flank without occlusive dressings, at 0.3 ml daily for28 days. Rats were fed ad libitum and housed in the same room in 4 cagesaccording to group. They were observed for condition and weighed daily.Food consumption was measured by residual weight of chow. Animals werefasted overnight prior to day 29, and Oral Glucose Tolerance Tests wereconducted on day 29 (1 g glucose per kg body weight). Skin tissue andserum chemistries were collected at day 29.

Results: Daily observations and skin condition were unremarkable. Therewere no differences in food consumption between treatment conditions.FIG. 7 shows mean weight gain, by group, for days 0 to 29. Compared tovehicle, topical latanoprost 0.5%, 0.05%, 0.005% caused a dose-dependentreductions in weight gain, which were statistically significant for the0.5% and 0.05% concentrations.

FIG. 8 shows representative histologic sections of skin and subcutaneousfat from untreated (left) and treated (right) flanks of animals assignedto vehicle only (Group 1), latanoprost 0.005% (Group 2), and latanoprost0.5% (Group 4). All sections are shown at the same magnification (scalebar at top right=500 microns). The surface of the skin is orientedtoward the top of each panel.

In vehicle-only treated animals (Group 1), subcutaneous adipose tissueconsisted of several pseudolayers of plump adipocytes, which extendedinto the reticular dermis and were occasionally seen interspersed withpanniculus muscle. The dermis was thick.

In animals treated with latanoprost 0.005%, the right (treated) flankfewer and smaller adipocytes, and a thinner adipose layer. Adipocyteswere not interspersed with dermis, and the dermis was thinner than invehicle-only animals. The untreated (left) flank resembled that of avehicle-treated animal, with a thick adipose layer and full adipocytes.This observation is consistent with a local effect, but not a systemiceffect, from topical latanoprost at a concentration of 0.005%.

In animals treated with topical latanoprost 0.5%, fewer and smalleradipocytes, and thinner adipose layer and dermis were seen on bothtreated and untreated flanks. The effects were symmetric, indicative ofa systemic effect.

FIG. 9 summarizes serum lipid levels by group, as measured on day 29.Compared to vehicle-treated control animals, latanoprost was associatedwith dose-dependent reductions in triglycerides and LDL, anddose-dependent increases in HDL and HDL:LDL ratio. These benefits wereseen at the 0.5% and 0.05% concentrations, and were absent at the 0.005%concentration. Because of the small sample size, these differences didnot reach statistical significance, except for the HDL:LDL ratio ofLatanoprost 0.5% vs. vehicle (one-sided p<0.05).

FIG. 10 shows the results of oral glucose tolerance testing on day 29.Latanoprost caused dose-dependent improvements in oral glucosetolerance, seen at the 0.5% and 0.05% concentrations (results for the0.005% concentration [not shown] were similar to control). As summarizedin FIG. 11, the serum glucose Area Under the Curve from 15 to 120minutes post-glucose load (AUC₁₅₋₁₂₀) was 12% and 26% lower in animalstreated with latanoprost 0.05% and 0.5%, respectively, compared tovehicle-treated animals. There was no effect on oral glucose tolerancewith latanoprost 0.005%.

Thus, in a rat model of obesity, dyslipidemia, and diabetes, theforegoing results show reduced weight gain, improved serum lipids, andimproved glucose tolerance following transdermal administration oflatanoprost at concentrations of 0.5% and 0.05%, but not 0.005%. Theseeffects were dose-dependent, and the minimum effective dose for theseeffects was deemed to be the 0.05% concentration.

Histology pointed to a systemic effect of latanoprost 0.5%, which wasnot seen with latanoprost 0.005%. Thus, although adipose tissue wasreduced by locally active treatment (e.g. by topical latanoprost0.005%), significant reductions in serum lipids and overall body weightappeared to occur only in response systemically active treatment (e.g.topical latanoprost 0.05% or 0.5%).

Example 3

FIG. 12 compares various topical doses of latanoprost in mouse, rat, andhuman, with respect to projected systemic dose. All calculations assumeonce-daily dosing and 100% serum bioavailability. The derivation of eachdose is set forth based on the animal body weight, drug concentration,and drug volume. Finally, doses are scaled allometrically for bodysurface area (mg/m²/d), as is appropriate for most low-molecular-weightmolecules.

In the rat, the minimum effective dose of topical latanoprost for lipid,diabetes, and obesity reduction, which was 0.05%, equivalent to 0.5mg/ml (Example 2), corresponds to a systemic dose of 3.6 mg/m²/d. Thisis corroborated in the mouse (Example 1), where serum lipids and obesityresponded to BIE, a close analog of latanoprost, at systemic doses of 10mg/m²/d; a minimum effective dose of BIE was not determined in themouse.

In humans, administration of a latanoprost eye drop (Xalatan®), which issufficient to reduce adipose tissue locally around the human eye,nonetheless involves a very low systemic dose of 0.008 mg/m²/d, or 0.016mg/m²/d if both eyes are treated. Thus, the recommended human ophthalmicdose, if both eyes are treated, is 450-fold lower than the minimumeffective dose for lipid and obesity reduction in the rat.

Without any wish to be bound by theory, by comparison to the minimumeffective dose of latanoprost in the rat, it is therefore predicted thata human transdermal dose of about 7 mg latanoprost per day would besufficient to achieve a systemic benefit for serum lipids, a diabeticcondition, and/or obesity. This could be delivered, for example, as adaily dose of 1 ml transdermal gel with a concentration 0.7% (w/v) or 7mg/ml latanoprost.

Example 4

The following description exemplifies preparation of a pharmaceuticalcomposition of latanoprost gel for transdermal administration to ahuman.

700 mg of pure latanoprost powder, made under Good ManufacturingPractice, is fully dissolved in 20 ml of an organic phase consisting oflecithin (about 10 ml), and isopropyl palmitate (about 10 ml). Into theorganic phase is slowly mixed 80 ml of an aqueous phase, previouslycooled to 4 degrees centrigrade, consisting of poloxamer 407 (about16-24 ml) and water (q.s.). Suitable preservatives (e.g., sorbic acid,potassium sorbate) are included in the formulation. The mixture is mixedwell at room temperature until a gel forms, and the mixture is thenprocessed through an ointment mill. About 100 ml of latanoprosttransdermal gel is obtained, at a 7 mg/ml or 0.7% concentration.

Example 5

The following description exemplifies preparation of a pharmaceuticalcomposition of latanoprost cream for transdermal administration to ahuman.

500 mg of pure latanoprost powder, made under Good ManufacturingPractice, is mixed in a mortar with 5 ml of ethoxy diglycol to form apaste. 100 ml of Lipoderm Base® (PCCA, Houston, Tex.) is addedgeometrically to the mortar. A suitable preservative such as potassiumsorbate is added. The mixture is transferred to an electric mortar andpestle and mixed at 2 rpm for 2 minutes. Optionally, the mixture is thenrun through an ointment mill on setting #2, then setting #1. About 100ml of latanoprost transdermal cream is obtained, at a 5 mg/ml or 0.5%concentration.

Example 6

The following description exemplifies preparation of a pharmaceuticalcomposition of latanoprost anhydrous liquid for transdermaladministration to a human.

630 mg of pure latanoprost powder, made under Good ManufacturingPractice, is mixed with 8.4 ml of benzyl alcohol, 33.6 ml of acetone,and isopropyl alcohol q.s. to 84 ml. The liquid is thoroughly mixed.About 84 ml of latanoprost transdermal liquid is obtained, at a 7.5mg/ml or 0.75% concentration.

Example 7

The following description exemplifies a clinical application of theinvention to treat obesity, dyslipidemia, and type 2 diabetes mellitusin a man with metabolic syndrome.

A 52-year-old man is suffers from obesity, dyslipidemia, and type 2diabetes. Medical evaluation reveals that his height is 5 feet 8 inchesand a weight of 240 pounds, corresponding to a body mass index (BMI) of36.5 (clinically obese). His waist circumference is 42 inches. Hisnoninvasive blood pressure is 184/98. His fasting serum glucose is 137g/dL and his glycated hemoglobin (hemoglobin A1C) is 8.1. Fasting serumlipids are as follows: triglycerides, 220 mg/dL; total cholesterol, 310mg/dL, LDL 240 mg/dL, HDL, 35 mg/dL. His physical exam is notable forprominent central (abdominal) obesity. In addition to medical therapy,the man's physician recommends a regimen of diet and exercise. After sixmonths the man's weight, hemoglobin A1C, serum glucose, and serum lipidsare unimproved. The physician prescribes systemic therapy withlatanoprost, for example, a transdermal 0.7% gel in a metered-dosedispenser, with instructions to apply 2 ml metered dose once daily tothe skin of the shoulders. After a period of time, for example from 1 to6 months, the man's weight is reduced. Serum glucose, hemoglobin A1C,fasting serum LDL, and fasting serum triglycerides also diminish.Fasting serum HDL rises.

Example 8

The following description exemplifies a clinical application of theinvention to reduce lipid concentrations in a patient with dyslipidemiaand a history of coronary artery disease and myocardial infarction.

A 67-year-old woman with a history of obesity, hyperlipidemia, coronaryartery disease, and myocardial infarction is found to have elevatedserum triglycerides, total cholesterol, and low density lipoprotein,despite use of a statin. The woman's physician prescribes an oral,extended-release formulation of tafluprost, for example, anextended-release tablet comprising 5 mg tafluprost, with instructions totake one capsule by mouth daily. After a period of time, for examplefrom 1 to 6 months, the woman's serum triglycerides, total cholesterol,and low density lipoprotein concentrations are reduced. Body weight isalso seen to improve.

Other Embodiments

All patents, patent applications, and literature references cited hereinare incorporated herein by reference.

The foregoing has been a description of certain non-limiting embodimentsof the invention. Those of ordinary skill in the art will appreciatethat various changes and modifications to this description may be madewithout departing from the spirit or scope of the present invention, asdefined in the following claims.

What is claimed is:
 1. A method for reducing body fat in an individual,the method comprising administering systemically to the skin of theindividual a pharmaceutical composition comprising a compound offormula:

or a pharmaceutically acceptable salt thereof, wherein the individualsuffers from an excess of body fat.
 2. The method of claim 1, whereinthe individual suffers from obesity.
 3. The method of claim 1, whereinthe body fat comprises subcutaneous fat.
 4. The method of claim 1,wherein the pharmaceutical composition is administered topically.
 5. Themethod of claim 1, wherein the pharmaceutical composition isadministered transdermally.
 6. The method of claim 1, wherein thepharmaceutical composition is administered to the skin in an implantabledepot.
 7. The method of claim 1, wherein the pharmaceutical compositionis administered to the skin in a sustained-release formulation.
 8. Themethod of claim 1, wherein the method reduces body weight.
 9. The methodof claim 1, wherein the method reduces weight gain.
 10. The method ofclaim 1, wherein the pharmaceutical composition further comprisestromethamine.
 11. The method of claim 1, wherein the pharmaceuticalcomposition comprises greater than or equal to 0.3% (w/v) of thecompound, or pharmaceutically acceptable salt thereof.
 12. The method ofclaim 1, wherein the pharmaceutical composition comprises between 0.3%and 10% (w/v), inclusive, of the compound, or pharmaceuticallyacceptable salt thereof.